Heterocyclic compounds useful as inhibitors of tyrosine kinases

ABSTRACT

Disclosed are novel compounds of formula (I):  
                 
 
     wherein Ar 1 , R a , R 4 , R 5 , X and Y are defined below, which are useful as inhibitors of certain protein tyrosine kinases and are thus useful for treating diseases associated with such kinases, for example, diseases resulting from inappropriate cell proliferation, which include autoimmune diseases, chronic inflammatory diseases, allergic diseases, transplant rejection and cancer, as well as conditions resulting from cerebral ischemia, such as stroke. Also disclosed are processes for preparing these compounds, novel intermediates useful in these processes and compositions comprising compounds of the formula (I).

[0001] This application is a divisional of U.S. application Ser. No.09/921,509, filed Aug. 2, 2001, which is a continuation-in-part of U.S.application Ser. No. 09/679,156, filed Oct. 5, 2000, which claimsbenefit from U.S. Provisional Application No. 60/157,922, filed Oct. 6,1999, all of which applications are herein incorporated by reference intheir entirety.

TECHNICAL FIELD OF THE INVENTION

[0002] This invention relates to substituted compounds of formula (I):

[0003] wherein Ar₁, R_(a), R₄, R₅, X and Y are defined below, which areuseful as inhibitors of certain protein tyrosine kinases and are thususeful for treating diseases resulting from inappropriate cellproliferation, which include autoimmune diseases, chronic inflammatorydiseases, allergic diseases, transplant rejection and cancer, as well asconditions resulting from cerebral ischemia, such as stroke. Thisinvention also relates to processes for preparing these compounds and topharmaceutical compositions comprising these compounds.

BACKGROUND OF THE INVENTION

[0004] Tyrosine kinases play an essential role in the regulation of cellsignaling and cell proliferation by phosphorylating tyrosine residues ofpeptides and proteins. Inappropriate activation of tyrosine kinases isknown to be involved in a variety of disease states, includingimmunologic and oncologic disorders.

[0005] It has been well established that T cells play an important rolein regulating the immune response (F. Powrie and R. L. Coffman, Immunol.Today, 1993, 14, 270). Activation of T cells is often the initiatingevent in many inflammatory and autoimmune diseases. In addition to theirrole in immune surveillance, T cells can become autoreactive byrecognizing self-antigens and thereby cause autoimmune disease such asrheumatoid arthritis and inflammatory bowel disease.

[0006] The T cell receptor (TCR) is the antigen-specific component ofthe T cell and is activated when the receptor is engaged with foreign orself-antigenic peptides. When the TCR is activated a series ofenzyme-mediated signal transduction cascades is initiated which resultsin the production of pro-inflammatory cytokines such as interleukin-2(IL-2).

[0007] The release of IL-2 is critically important since this lymphokineis required for T-lymphocyte proliferation, differentiation, andeffector function. Clinical studies have shown that interference withIL-2 activity effectively suppresses immune response in vivo (T. A.Waldmann, Immunol. Today, 1993, 14, 270). Accordingly, agents whichinhibit T-lymphocyte activation and subsequent IL-2 production, or blockthe activity of IL-2 are therapeutically useful for selectivelysuppressing immune response in a patient in need of suchimmunosuppression.

[0008] The eight members of the src family of tyrosine kinases are src,lck, fyn, lyn, hck, fgr, blk and yes (J. B. Bolen, J. S. Brugge, Ann.Rev. Immunol., 1997, 15, 371). These can be divided into 2 groups basedon their pattern of tissue expression. Src, fyn and yes have a broaddistribution while expression of lck, lyn, hck, fgr, and blk is largelylimited to hemopoietic cells. The therapeutic effects of inhibitingkinases of the src family can be ascertained by linking functionaldefects seen in gene disruption studies in mice. Src(−/−) mice hadsevere abnormalities in bone remodeling. Inhibition of src may thereforebe useful in treating osteoporosis. Lck(−/−) mice display a completelack of CD4+ cells and are unable to mount antigen-dependent immuneresponses.

[0009] A kinase of particular interest is p56lck, which is onlyexpressed in T-cells. Within the TCR signal transduction cascade thetyrosine kinase p56lck is a required element to initiate the activationresponse from the TCR intracellular domains to other signaling proteins.For example, T cells which lack the p56lck protein are unable to signalthrough the T cell receptor (D. B. Straus and A. Weiss, Cell, 1992, 70,585). Transfection of p56lck back into these cell lines restores TCRresponsiveness. Also, it has been shown in mice that inactivation of thep56lck gene leads to lack of proper thymocyte development (T. J. Molinaet al., Nature, 1992, 357, 161).

[0010] The conclusion drawn from these studies is that p56lck plays acrucial role in T cell maturation and antigen-induced T-cell activation.Therefore, an agent blocking p56lck would effectively block T cellfunction, act as an immunosuppressive agent and have potential utilityin autoimmune diseases, for example rheumatoid arthritis, multiplesclerosis, lupus, transplant rejection and allergic diseases (J. H.Hanke et al., Inflamm. Res., 1995, 44, 357).

[0011] Inhibitors of other members of the src family of non-receptortyrosine kinases are also useful for treating various disease states.Src is present in osteoclasts, and is important in bone remodeling. Forexample, inactivation of p60src diminishes bone resorption byosteoclasts (P. Soriano et al., Cell 1991, 64, 693, B. F. Boyce et al.J. Clin. Invest 1992, 90, 1622), it is therefore possible thatinhibitors of the kinase activity of p60src are useful in the treatmentof osteoporosis, Paget's disease and inflammation of bones and joints.Src kinases have been found to be activated in tumors, including breastand colon cancers, melanoma and sarcoma. For example, a number ofprimary tumors and tumor cell lines from patients with breast cancer,colon cancer, melanoma and sarcoma have been shown to have elevated srckinase activity, and activating src mutations are seen in some advancedcolon cancers. Inhibitors of src kinase had significantantiproliferative activity against cancer cell lines (M. M. Moasser etal., Cancer Res., 1999, 59, 6145) and inhibited the transformation ofcells to an oncogenic phenotype (R. Kami et al., Oncogene, 1999, 18,4654) suggesting that src kinase inhibitors may be useful anti-canceragents.

[0012] Src inhibitors have also been reported to be effective in ananimal model of cerebral ischemia (R. Paul et al. Nature Medicine 2001,7, 222), suggesting that src kinase inhibitors may thus be useful intreating conditions involving cerebral ischemia. For example, src kinaseinhibitors may be useful in reducing brain damage following stroke.

[0013] In addition, src family kinases participate in signaltransduction in several cell types. For example, fyn, like lck, isinvolved in T-cell activation. Hck and fgr are involved in Fc gammareceptor mediated oxidative burst of neutrophils. Src and lyn arebelieved to be important in Fc epsilon induced degranulation of mastcells, and so may play a role in asthma and other allergic diseases. Thekinase lyn is known to be involved in the cellular response to DNAdamage induced by UV light (T. Hiwasa, FEBS Lett. 1999, 444, 173) orionizing radiation (S. Kumar, J. Biol Chem, 1998, 273, 25654).Inhibitors of lyn kinase may thus be useful as potentiators in radiationtherapy.

[0014] Platelet derived growth factor is a potent mitogen for smoothmuscle cells. Its receptor (PDGFR) is a member of the receptor tyrosinekinase family (L. Claesson-Welsh, J. Biol Chem, 1994, 269, 32023). PDGFis involved in atherosclerosis and restenosis (K. E. Bornfeldt, TrendsCardiovasc. Med., 1996, 6, 143). In addition, receptor tyrosine kinasesincluding PDGFR kinase have been implicated as contributing factors incancer (A. Levitzki and A. Gazit, Science, 1995, 267, 1782) includingovarian (M. B. Dabrow et al., Gynecologic Oncology, 1998, 71, 29) andprostate (S. M. Sintich et al., Endocrinology, 1999, 140, 3411) cancersand glioblastoma (B. J. Silver, BioFactors, 1992 3, 217). Inhibitors ofPDGFR kinase are thus useful in the treatment of fibrotic diseases,restenosis and PDGF-dependent tumors.

[0015] Reports have appeared in the literature of agents that inhibitthe kinase activity of p56lck kinase and thus inhibit T cell activation.These include the natural product lavendustin A, and analogs (M. S.Smyth, J. Med. Chem., 1993, 36, 3010), the natural product damnacanthal(C. R. Faltynek et al., Biochemistry, 1995, 34, 12404), and a 1-methoxyagroclavine isolated from a fungal extract (R. Padmanabha et al.Bioorganic and Med. Chem. Letters, 1998, 8, 569). Other inhibitorsreported include WIN 61651 (J. Enzyme Inhibition, 1995, 9, 111)pyrazolopyrimidines PP1 and PP2 (Hanke et al. J. Biol Chem, 1996, 271,695) and indanone and indandione derivatives (J. L. Bullington et al.,Bioorganic and Med. Chem. Letters, 1998, 8, 2489).

[0016] A. P. Spader et al. (WO 98/54157, 1998) describe quinoline andquinoxaline compounds that inhibit p56lck and PDGFR kinase. Fusedpolycyclic 2-aminopyrimidine derivatives that inhibit p56lck arereported by J. M. Davis et al. (WO 98/28281, 1998). J. Das et al. claima series of benzothiazole amides as inhibitors of lck and other srcfamily kinases (WO 99/24035, 1999). Inhibitors of PDGFR kinase andsrc-family kinases were reviewed by H. D. H. Showalter, A. J. Kraker,Pharmacol. Ther., 1997, 76, 55. Several patents on inhibitors of lck arereviewed in P. M. Traxler, Exp. Opin. Ther. Patents, 1997, 7, 571,and P.M. Traxler, Exp. Opin. Ther. Patents, 1998, 8, 1599.

[0017] U.S. Pat. No. 4,176,184 discloses imidazoisoquinoline-diones,which are described as being useful as cardiotonics, hypotensives,antithrombotics and antiarrhythmics. DE 3410168 A1 disclosesimidazoisoquinoline-dione derivatives, these compounds are described asbeing useful as cardiotonic agents in which the substituent on the fusedimidazole ring is a pyridine ring bridged to the imidazole carbon by aC₁-C₄ alkyl group, a vinyl group or a chemical bond. EP 322 746 A1discloses heterocyclic lactam derivatives described as being useful ascardiotonic agents, antihypertensive agents and vasodilators.

[0018] The compounds of the present invention represent a novelstructural class, which is distinct from previously reported tyrosinekinase inhibitors.

BRIEF SUMMARY OF THE INVENTION

[0019] The work cited above supports the principle that inhibition ofthe kinases mentioned above will be beneficial in the treatment ofvarious disease states.

[0020] It is therefore an object of the invention to provide novelcompounds which inhibit PDGFR kinase and the src-family kinasesincluding lck, src, fyn, lyn, hck, fgr, blk and yes.

[0021] It is a further object of the invention to provide methods fortreating diseases and pathological conditions mediated by src-familytyrosine kinases and PDGFR kinase such as autoimmune diseases,transplant rejection, psoriasis, osteoporosis, Paget's disease, cancer,including src-dependent tumors and PDGF-dependent tumors, cerebralischemic conditions, atherosclerosis, restenosis and allergic diseases,using the novel compounds of the invention.

[0022] It is yet a further object of the invention to provide processesof preparation of the above-mentioned novel compounds and pharmaceuticalcompositions comprising the same.

DETAILED DESCRIPTION OF THE INVENTION

[0023] The src-family tyrosine kinases and PDGFR kinase discussed aboveexhibit some homology in their amino acid structure. It is contemplatedthat due to structural differences between individual src-family kinasesand PDGFR kinase, different compounds of the invention may havedifferent inhibitory potencies against individual tyrosine kinases. Thussome of compounds of the invention may also be expected to be mosteffective in treating diseases mediated by tyrosine kinases that theyinhibit most potently. Particular compounds disclosed herein have beenshown to be active inhibitors of p56lck kinase, p60src kinase and PDGFRkinase. See the section entitled “Assessment of Biological Properties”disclosed herein.

[0024] In its broadest generic aspect, the invention provides novelcompounds of the formula I:

[0025] wherein:

[0026] Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocycle isoptionally substituted by one or more R₁, R₂ and R₃;

[0027] X is NH, N—C₁₋₃alkyl, N-cyclopropyl, S or O;

[0028] Y is NR₁₅, S or O;

[0029] R_(a) is H, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₁₀alkynyl, each ofwhich may be branched or cyclic; or R_(a) is aryl or heteroaryl; whereineach R_(a) is independently optionally substituted with one or moreC₁₋₆alkyl, C₁₋₆ alkoxy, halogen, OH, oxo, NR₁₀R₁₁, aryl or heteroaryl,each aryl or heteroaryl being optionally substituted with one or moregroups selected from halogen, OH, C₁₋₃alkyl, C₁₋₃alkoxy,hydroxyC₁₋₃alkyl and (CH₂)_(m)NR₁₀R₁₁; and wherein R_(a) is attached atthe 4- or 5- position;

[0030] R₁ and R₂ are the same or different and selected from H, halogen,CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturated alkyl,C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranched acyl,C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₁₀R₁₁, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabovementioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from oxo, OH, NR₁₀R₁₁, C₁₋₆ branched or unbranched alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl;

[0031] R₃ is H, halogen, OH, (CH₂)_(n)NR₁₀R₁₁, CONR₁₀R₁₁,(CH₂)_(n)CO₂R₁₂; C₁₋₃alkyl optionally substituted with OH, C₁₋₃ alkoxyoptionally halogenated or C₁₋₃ alkylthio;

[0032] R₄ and R₅ together with the atoms to which they are attachedcomplete a fused ring system of the formulas A or B:

[0033] R₆ is C₁₋₃alkyl or H;

[0034] R₇ is C₁₋₆alkyl branched or unbranched or H;

[0035] R₈ is H, C₁₋₆alkyl branched or unbranched, saturated orunsaturated, optionally substituted with phenyl, OH or C₁₋₃alkoxy; or R₈is (CH₂)_(m)NR₁₀R₁₁, (CH₂)_(m)NR₁₀COR₁₂, (CH₂)_(n)CO₂R₁₂,(CH₂)_(n)CONR₁₀R₁₁; or R₈ is phenyl or heteroaryl, each being optionallysubstituted with C₁₋₃alkyl, C₁₋₃alkoxy, OH, —SO₃H or halogen;

[0036] R₉ is H, CN or CONR₁₀R₁₁; or R₉ is C₁₋₁₀alkyl branched orunbranched, C₃₋₁₀cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆alkynyl each being optionally substituted with one or moreC₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, halogen, OH,oxo, CN, C₁₋₃alkoxy, C₁₋₃acyloxy, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁,NR₁₀C(═NR₁₀)NR₁₀R₁₁, NR₁₀COR₁₂, NR₁₀S(O)_(p)R₁₂, SR₁₂, CONR₁₀R₁₁,CO₂R₁₂, C(R₁₀)═NNR₁₀R₁₁,

[0037] C(R₁₀)═NNR₁₀CONR₁₀R₁₁, aryloxy, arylthio, aryl or heteroaryl;wherein each aryloxy, arylthio, aryl or heteroaryl is optionallysubstituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₁₀R₁₁ orO(CH₂)₂₋₄NR₁₀R₁₁;

[0038] or R₉ is aryl, heteroaryl, or heterocycle, wherein each aryl,heteroaryl or heterocycle is optionally substituted with one to threegroups selected from C₁₋₃alkyl optionally substituted with phenyl orNR₁₀C(═NR₁₀)NR₁₀R₁₁, C₁₋₃alkoxy, halogen, CN, oxo, (CH₂)_(n)NR₁₀R₁₁,(CH₂)_(n)CO₂R₁₂; (CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0039] or R₈ and R₉ together form a saturated or unsaturated 5 or 6membered aromatic or nonaromatic carbocyclic ring optionally substitutedby one or two C₁₋₃alkyl, OH, oxo or (CH₂)_(n)NR₁₀R₁₁, or optionallyspiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3dioxolane group or 1,3 dithiolane group optionally substituted byC₁₋₆alkyl, C₁₋₆alkoxy, OH or (CH₂)_(n)NR₁₀R₁₁;

[0040] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl and heteroaryl; whereinsaid alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl or heteroaryl are optionallysubstituted with OH, C₁₋₃alkoxy, CN, NO₂, C₁₋₃acyloxy, CO₂R₁₂, NR₁₃R₁₄,O(CH₂)₂₋₄NR₁₃R₁₄, aryl or heteroaryl;

[0041] or R₁₀ and R₁₁ together form a 3-7 member alkylene chaincompleting a ring about the N atom to which they are attached; whereinsaid alkylene chain is optionally interrupted by O, S(O)_(p), and NR₁₃;and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, OH, —(CH₂)_(n)NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄;

[0042] R₁₂ is H, C₁₋₆alkyl or C₃₋₈cycloalkyl wherein each alkyl orcycloalkyl is optionally substituted with phenyl, OH, C₁₋₃alkoxy orNR₁₃R₁₄; or R₁₂ is phenyl or heterocycle, optionally substituted withone to three groups selected from C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₁₀R₁₁, (CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0043] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0044] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0045] R₁₅is H or C₁₋₃ alkyl;

[0046] m is 1-4; n is 0-3 and p is 0-2; and

[0047] the pharmaceutically acceptable acid or salt derivatives thereof.

[0048] In one embodiment of the invention, there are provided compoundsof the formula (I) described above, wherein:

[0049] Ar₁ is

[0050] a) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl;

[0051] b) a cycloalkenyl group selected from cyclopentenyl,cyclohexenyl, cycloheptenyl;

[0052] c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, fluorenyl;

[0053] d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or

[0054] e) a heterocycle selected from pyrrolinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, piperazinyl and indolinyl;

[0055] wherein each of the above Ar₁ are optionally substituted by oneor more R₁, R₂ and R₃;

[0056] R_(a) is H, C₁₋₆alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, phenyl orheteroaryl selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl and thienyl; eachR_(a) being optionally substituted with one or more phenyl, halogen,C₁₋₃alkyl, C₁₋₃ alkoxy, OH, oxo, or NR₁₀R₁₁; wherein R_(a) is at the4-position;

[0057] R₁ and R₂ are as hereinabove defined;

[0058] R₃ is H, halogen, methyl, methoxy, hydroxymethyl or OH;

[0059] R₈ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, optionally substituted with OH; or R₈ is (CH₂)₂₋₃NR₁₀R₁₁,(CH₂)_(n)CO₂R₁₂ or (CH₂)_(n)CONR₁₀R₁₁;

[0060] R₉ is CN or CONR₁₀R₁₁; or R₉ is C₁₋₃alkyl branched or unbranched,C₂₋₄ alkenyl, C₂₋₄alkynyl each being optionally substituted with one ormore C₅₋₇cycloalkyl, C₅₋₇ cycloalkylidene, C₅₋₇cycloalkenyl,OH, CN,C₁₋₃acyloxy, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀C(═NR₁₀)NR₁₀R₁₁, NR₁₀COR₁₂,NR₁₀S(O)_(p)R₁₂, CONR₁₀R₁₁, CO₂R₁₂, C(R₁₀)═NNR₁₀R₁₁,C(R₁₀)═NNR₁₀CONR₁₀R₁₁, aryl or heteroaryl; wherein each aryl orheteroaryl is optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy,halogen, (CH₂)_(n)NR₁₀R₁₁ or O(CH₂)₂₋₄NR₁₀R₁₁;

[0061] or R₉ is aryl,heteroaryl or heterocycle, each optionallysubstituted with one to three groups selected from C₁₋₃alkyl optionallysubstituted with phenyl or NR₁₀C(═NR₁₀)NR₁₀R₁₁, C₁₋₃alkoxy, halogen, CN,oxo, (CH₂)_(n)NR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂; (CH₂)_(n)CONR₁₀R₁₁ andO(CH₂)₂₋₄NR₁₀R₁₁;

[0062] or R₈ and R₉ together form a saturated or unsaturated 5 or 6membered aromatic or nonaromatic carbocyclic ring optionally substitutedby C₁₋₃alkyl or OH, or optionally spiro-fused to a 1,3 dioxolane groupor 1,3 dithiolane group, each 1,3 dioxolane group or 1,3 dithiolanegroup optionally substituted by C₁₋₃alkyl, C₁₋₃alkoxy, OH or(CH₂)_(n)NR₁₀R₁₁;

[0063] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, benzyl and phenyl; wherein said alkyl,cycloalkyl, benzyl or phenyl are optionally substituted with OH,C₁₋₃alkoxy, C₁₋₃acyloxy, CN, NO₂, CO₂R₁₂, NR₁₃R₁₄, O(CH₂)₂₋₄NR₁₃R₁₄ orphenyl;

[0064] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, OH, —(CH₂)_(n)NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄;;

[0065] R₁₂ is H, C₁₋₆alkyl or C₅₋₇cycloalkyl, each optionallysubstituted with phenyl, OH, C₁₋₃alkoxy or NR₁₃R₁₄; or R₁₂ is phenyl orheterocycle, each optionally substituted with one to three groupsselected from C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(m)NR₁₀R₁₁,(CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0066] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0067] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; and

[0068] R₁₅ is H.

[0069] In another embodiment, there are provided compounds of theformula (I) described immediately above, wherein:

[0070] Ar₁ is phenyl, or pyridyl, wherein each is optionally substitutedby one or more

[0071] R₁, R₂ and R₃ as defined below;

[0072] X is NH or N—CH₃;

[0073] Y is NH and

[0074] R_(a) is H, hydroxyC₁₋₂alkyl, 2-hydroxyethylaminomethyl,methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl,3-hydroxy-2-oxo-propyl, vinyl or C₃₋₅alkynyl substituted by C₁₋₃alkoxyor phenyl;

[0075] R₁ and R₂ are the same or different and selected from: H,halogen, C₁₋₃ alkyl, wherein the C₁₋₃ alkyl are optionally partially orfully halogenated, NO₂, NR₁₃R₁₄;

[0076] R₃ is H, halogen, methoxy or methyl;

[0077] R₄ and R₅ together complete a fused ring of formula B;

[0078] R₈ is H, C₁₋₃alkyl optionally substituted with OH; or R₈ is(CH₂)₂₋₃NR₁₀R₁₁ or CO₂R₁₂;

[0079] R₉ is CN; or R₉ is methyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl, eachbeing optionally substituted with one or more C₅₋₇ cycloalkylidene,C₅₋₇cycloalkenyl, OH, CN, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀COR₁₂,NR₁₀S(O)_(p)R₁₂, CONR₁₀R₁₁, CO₂R₁₂, C(R₁₀)═NNR₁₀R₁₁ or heteroaryl;

[0080] or R₉ is aryl or heteroaryl optionally substituted with one tothree groups selected from C₁₋₃alkyl optionally substituted with phenyl,C₁₋₃alkoxy, halogen, amino or CONH₂;

[0081] or R₈ and R₉ together form a cyclopentene ring spiro-fused to a1,3 dioxolane group, said 1,3 dioxolane group being optionallysubstituted by C₁₋₃alkyl, C₁₋₃alkoxy, OH or (CH₂)_(n)NR₁₀R₁₁;

[0082] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₃alkyl branched orunbranched, C₅₋₇cycloalkyl or phenyl, wherein said alkyl, cycloalkyl orphenyl are optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, NO₂,CO₂R₁₂, NR₁₃R₁₄, O(CH₂)₂₋₄NR₁₃R₁₄ or phenyl;

[0083] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy,OH, (CH₂)_(n)NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄;

[0084] R₁₂ is H, C₁₃alkyl or C₅₋₇cycloalkyl, each optionally substitutedwith phenyl, OH, C₁₋₃alkoxy or NR₁₃R₁₄; or R₁₂ is phenyl or is asaturated, 4- to 6-membered nitrogen-containing heterocycle, eachoptionally substituted with one to three groups selected from C₁₃alkyl,C₁₃alkoxy, halogen, (CH₂)_(m)NR₁₀R₁₁, (CH₂)_(n)CONR₁₀R₁₁ andO(CH₂)₂₋₄NR₁₀R₁₁;

[0085] R₁₃ and R₁₄ are each independently selected from H and C₁₋₃alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0086] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0087] In yet another embodiment, there are provided compounds of theformula (I) described immediately above, wherein:

[0088] Ar₁ is phenyl;

[0089] R_(a) is H or hydroxymethyl;

[0090] R₁ and R₂ are the same or different and selected from: halogen,methyl optionally partially or fully halogenated, NO₂ and NH₂;

[0091] R₃ is H, chloro, fluoro, bromo or methoxy;

[0092] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, methoxy, C₁₋₃alkyl branched orunbranched or C₅₋₇cycloalkyl, wherein said alkyl or cycloalkyl areoptionally substituted with OH, NR₁₃R₁₄ or phenyl;

[0093] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₂ alkyl,NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄; and

[0094] R₁₂ is C₁₋₃alkyl optionally substituted with morpholino; or R₁₂is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionallysubstituted with one to three groups selected from C₁₋₃alkyl, C₁₋₃alkoxyand halogen.

[0095] In another subgeneric aspect, the invention provides novelcompounds of the formula I:

[0096] wherein:

[0097] Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocyle isoptionally substituted by one or more R₁, R₂ and R₃;

[0098] X is NH, N—C₁₋₃alkyl, N-cyclopropyl, S or O;

[0099] Y is NR₁₅, S or O;

[0100] R_(a) is H, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₁₀alkynyl, each ofwhich may be branched or cyclic; or R_(a) is aryl or heteroaryl; whereineach R_(a) is independently optionally substituted with one or moreC₁₋₃alkyl, C₁₋₆ alkoxy, halogen, OH, oxo, NR₁₀R₁₁, aryl or heteroaryleach aryl or heteroaryl being optionally substituted with one or moregroups selected from halogen, OH, C₁₋₃alkyl, C₁₋₃alkoxy,hydroxyC₁₋₃alkyl and (CH₂)_(m)NR₁₀R₁₁; and wherein R_(a) is attached atthe 4- or 5- position;

[0101] R₁ and R₂ are the same or different and selected from H, halogen,CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturated alkyl,C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranched acyl,C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₁₀R₁₁, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabove mentioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from oxo, OH, NR₁₀R₁₁, C₁₋₆ branched or unbranched alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl;

[0102] R₃ is H, halogen, OH, (CH₂)_(n)NR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂;C₁₋₃alkyl optionally substituted with OH, C₁₋₃ alkoxy optionallyhalogenated or C₁₋₃ alkylthio;

[0103] R₄ and R₅ together with the atoms to which they are attachedcomplete a fused ring system of the formulas A or B:

[0104] R₆ is C₁₋₃alkyl or H;

[0105] R₇ is C₁₋₆alkyl branched or unbranched or H;

[0106] R₈ is H, C₁₋₆ alkyl branched or unbranched, saturated orunsaturated, optionally substituted with phenyl, OH or C₁₋₃alkoxy; or R₈is (CH₂)_(m)NR₁₀R₁₁, (CH₂)_(m)NR₁₀COR₁₂, (CH₂)_(n)CO₂R₁₂,(CH₂)_(n)CONR₁₀R₁₁; or R₈ is phenyl or heteroaryl, each being optionallysubstituted with C₁₋₃alkyl, C₁₋₃alkoxy, OH, —SO₃H or halogen;

[0107] R₉ is H; or R₉ is C₁₋₁₀alkyl branched or unbranched, C₃₋₁₀cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl each being optionally substitutedwith one or more halogen, OH, oxo, CN, C₁₋₃alkoxy, NR₁₀R₁₁, NR₁₀COR₁₂,SR₁₂, CONR₁₀R₁₁, CO₂R₁₂, aryloxy, arylthio, aryl or heteroaryl; whereineach aryloxy, arylthio, aryl or heteroaryl is optionally substitutedwith C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₁₀R₁₁ orO(CH₂)₂₋₄NR₁₀R₁₁;

[0108] or R₉ is aryl or heteroaryl, wherein each aryl or heteroaryl isoptionally substituted with one to three groups selected from C₁₋₃alkyloptionally substituted with phenyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂; (CH₂)_(n)CONR₁₀R₁₁ andO(CH₂)₂₋₄NR₁₀R₁₁;

[0109] or R₈ and R₉ together form a saturated or unsaturated 6 memberedaromatic or nonaromatic carbocyclic ring optionally substituted by oneor two OH, oxo or (CH₂)_(n)NR₁₀R₁₁ ;

[0110] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl and heteroaryl; whereinsaid alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl or heteroaryl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₂, NR₁₃R₁₄,O(CH₂)₂₋₄NR₁₃R₁₄, aryl or heteroaryl;

[0111] or R₁₀ and R₁₁ together form a 3-7 member alkylene chaincompleting a ring about the N atom to which they are attached; whereinsaid alkylene chain is optionally interrupted by O, S(O)p, and NR₁₃; andwherein said ring is optionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy,OH or —(CH₂)_(n)NR₁₃R₁₄;

[0112] R₁₂ is H, C₁₋₆alkyl or C₃₋₈cycloalkyl wherein each alkyl orcycloalkyl is optionally substituted with phenyl, OH, C₁₋₃alkoxy orNR₁₃R₁₄; or R₁₂ is phenyl, optionally substituted with one to threegroups selected from C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₁₀R₁₁,(CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0113] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0114] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0115] R₁₅ is H or C₁₋₃ alkyl;

[0116] m is 1-4, n is 0-3 and p is 0-2; and

[0117] the pharmaceutically acceptable acid or salt derivatives thereof.

[0118] In one embodiment of the invention, there are provided compoundsof the formula (I) as described immediately above, and wherein:

[0119] Ar₁ is

[0120] a) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl;

[0121] b) a cycloalkenyl group selected from cyclopentenyl,cyclohexenyl, cycloheptenyl;

[0122] c) phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, fluorenyl;

[0123] d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl,or a fusedheteroaryl selected from cyclopentenopyridine, cyclohexanopyridine,cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine,cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine,cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline,cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole,cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or

[0124] e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, piperazinyl and indolinyl;

[0125] wherein each of the above Ar₁ are optionally substituted by oneor more R₁, R₂ and R₃ as hereinabove defined;

[0126] R_(a) is H, C₁₋₆ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, phenyl orheteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl andthienyl; each R_(a) being optionally substituted with one or morephenyl, halogen, C₁₋₃alkyl, C₁₋₃ alkoxy, OH, oxo, or NR₁₀R₁₁; whereinR_(a) is at the 4-position;

[0127] R₃ is H, halogen, methyl, methoxy, hydroxymethyl or OH;

[0128] R₈ is H, C₁₋₃alkyl branched or unbranched, saturated orunsaturated, optionally substituted with OH; or R₈ is (CH₂)₂₋₃NR₁₀R₁₁,(CH₂)_(n)CO₂R₁₂ or (CH₂)_(n)CONR₁₀R₁₁;

[0129] R₉ is C₁₋₃alkyl branched or unbranched, C₂₋₄ alkenyl, C₂₋₄alkynyleach being optionally substituted with one or more OH, CN, NR₁₀R₁₁,CONR₁₀R₁₁, CO₂R₁₂, aryl or heteroaryl; wherein each aryl or heteroarylis optionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₁₀R₁₁ or O(CH₂)₂₋₄NR₁₀R₁₁;

[0130] or R₉ is aryl or heteroaryl optionally substituted with one tothree groups selected from C₁₋₃alkyl optionally substituted with phenyl,C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂;(CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0131] or R₈ and R₉ together form a saturated or unsaturated 6 memberedaromatic or nonaromatic carbocyclic ring optionally substituted by OH;

[0132] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, benzyl and phenyl;

[0133] wherein said alkyl, cycloalkyl, benzyl or phenyl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₂, NR₁₃R₁₄,O(CH₂)₂₋₄NR₁₃R₁₄ or phenyl;

[0134] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₃R₁₄;

[0135] R₁₂ is H or C₁₋₆alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₃R₁₄;

[0136] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0137] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; and

[0138] R₁₅is H.

[0139] In another embodiment of the invention, there are providedcompounds of the formula (I) as described immediately above, andwherein:

[0140] Ar₁ is phenyl, or pyridyl;

[0141] X is NH or N—CH₃;

[0142] Y is NH and

[0143] R_(a) is H, hydroxyC₁₋₂alkyl, 2-hydroxyethylaminomethyl,methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl,3-hydroxy-2-oxo-propyl, vinyl or C₃₋₅alkynyl substituted by C₁₋₃alkoxyor phenyl;

[0144] R₁ and R₂ are the same or different and selected from: halogen,C₁₋₃ alkyl, wherein the C₁₋₃ alkyl are optionally partially or fullyhalogenated, NO₂, NR₁₃R₁₄;

[0145] R₃ is H, halogen, methoxy or methyl;

[0146] R₄ and R₅ together complete a fused ring of formula B;

[0147] R₈ is H, C₁₋₃alkyl optionally substituted with OH; or R₈ is(CH₂)₂₋₃NR₁₀R₁₁ or CO₂R₁₂;

[0148] R₉ is methyl or C₂₋₃ alkenyl each being optionally substitutedwith one or more OH, CN, NR₁₀R₁₁, CONR₁₀R₁₁ or CO₂R₁₂;

[0149] or R₉ is heteroaryl optionally substituted with one to threegroups selected from C₁₋₃alkyl optionally substituted with phenyl,C₁₋₃alkoxy, halogen or amino;

[0150] is R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₃alkyl branched orunbranched, optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy,CO₂R₁₂, NR₁₃R₁₄, O(CH₂)₂₋₄NR₁₃R₁₄ or phenyl;

[0151] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy or OH;

[0152] R₁₂ is H or C₁₋₃alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₃R₁₄;

[0153] R₁₃ and R₁₄ are each independently selected from H and C₁₋₃alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0154] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0155] In yet another embodiment of the invention there are providedcompounds of the formula (T) as described immediately above, andwherein:

[0156] Ar₁ is phenyl;

[0157] R_(a) is H or hydroxymethyl;

[0158] R₁ and R₂ are the same or different and selected from: halogen,methyl optionally partially or fully halogenated, NO₂ and NH₂;

[0159] R₃ is H, chloro, fluoro, bromo or methoxy;

[0160] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, methoxy, C₁₋₃alkyl branched orunbranched, optionally substituted with OH, NR₁₃R₁₄ or phenyl;

[0161] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₂ alkyl;and

[0162] R₁₂ is C₁₋₃alkyl optionally substituted with morpholino.

[0163] In still another embodiment of the invention there are providedcompounds of the formula (Ia):

[0164] wherein:

[0165] X is NH, N—C₁₋₃alkyl, N-cyclopropyl, S or O;

[0166] R_(a) is H, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂l₀alkynyl, each ofwhich may be branched or cyclic; or R_(a) is aryl or heteroaryl;

[0167] wherein each R_(a) is independently optionally substituted withone or more C₁₋₆alkyl, C₁₋₆ alkoxy, halogen, OH, oxo, NR₁₀R₁₁, aryl orheteroaryl each aryl or heteroaryl being optionally substituted with oneor more groups selected from halogen, OH, C₁₋₃alkyl, C₁₋₃alkoxy,hydroxyC₁₋₃alkyl and (CH₂)_(m)NR₁₀R₁₁; and wherein R_(a) is attached atthe 4- or 5-position;

[0168] R₁ and R₂ are the same or different and selected from H, halogen,CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturated alkyl,C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranched acyl,C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₁₀R₁₁, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabovementioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from oxo, OH, NR₁₀R₁₁, C₁₋₆ branched or unbranched alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl;

[0169] R₃ is H, halogen, OH, (CH₂)_(n)NR₁₀R₁₁, CONR₁₀R₁₁,(CH₂)_(n)CO₂R₁₂; C₁₋₃alkyl optionally substituted with OH, C₁₋₃ alkoxyoptionally halogenated or C₁₋₃ alkylthio;

[0170] R₄ and R₅ together with the atoms to which they are attachedcomplete a fused ring system of the formulas A or B:

[0171] R₆ is C₁₋₃alkyl or H;

[0172] R₇ is C₁₋₆alkyl branched or unbranched or H;

[0173] R₈ is H, C₁₋₆alkyl branched or unbranched, saturated orunsaturated, optionally substituted with phenyl, OH or C₁₋₃alkoxy; or R₈is (CH₂)_(m)NR₁₀R₁₁, (CH₂)_(m)NR₁₀COR₁₂, (CH₂)_(n)CO₂R₁₂,(CH₂)_(n)CONR₁₀R₁₁ or R₈ is phenyl or heteroaryl, each being optionallysubstituted with C₁₋₃alkyl, C₁₋₃alkoxy, OH, —SO₃H or halogen;

[0174] R₉ is H, CN or CONR₁₀R₁₁; or R₉ is C₁₋₁₀alkyl branched orunbranched, C₃₋₁₀cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆alkynyl each being optionally substituted with one or moreC₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, halogen, OH,oxo, CN, C₁₋₃alkoxy, C₁₋₃acyloxy, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁,NR₁₀C(═NR₁₀)NR₁₀R₁₁, NR₁₀COR₁₂, NR₁₀S(O)_(p)R₁₂, SR₁₂, CONR₁₀R₁₁,CO₂R₁₂, C(R₁₀)═NNR₁₀R₁₁, C(R₁₀)═NNR₁₀CONR₁₀R₁₁, aryloxy, arylthio, arylor heteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl isoptionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₁₀R₁₁ or O(CH₂)₂₋₄NR₁₀R₁₁;

[0175] or R₉ is aryl, heteroaryl, or heterocycle, wherein each aryl,heteroaryl or heterocycle is optionally substituted with one to threegroups selected from C₁₋₃alkyl optionally substituted with phenyl orNR₁₀C(═NR₁₀)NR₁₀R₁₁, C₁₋₃alkoxy, halogen, CN, oxo, (CH₂)_(n)NR₁₀R₁₁,(CH₂)_(n)CO₂R₁₂; (CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0176] or R₈ and R₉ together form a saturated or unsaturated 5 or 6membered aromatic or nonaromatic carbocyclic ring optionally substitutedby one or two C₁₋₃alkyl, OH, oxo or (CH₂)_(n)NR₁₀R₁₁, or optionallyspiro-fused to a 1,3 dioxolane group or 1,3 dithiolane group, each 1,3dioxolane group or 1,3 dithiolane group optionally substituted byC₁₋₆alkyl, C₁₋₆alkoxy, OH or (CH₂)_(n)NR₁₀R₁₁;

[0177] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl and heteroaryl; whereinsaid alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl or heteroaryl are optionallysubstituted with OH, C₁₋₃alkoxy, CN, NO₂, C₁₋₃acyloxy, CO₂R₁₂, NR₁₃R₁₄,O(CH₂)₂₋₄NR₁₃R₁₄, aryl or heteroaryl;

[0178] or R₁₀ and R₁₁ together form a 3-7 member alkylene chaincompleting a ring about the N atom to which they are attached; whereinsaid alkylene chain is optionally interrupted by O, S(O)_(p), and NR₁₃;and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, OH, —(CH₂)_(n)NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄;

[0179] R₁₂ is H, C₁₋₆alkyl or C₃₋₈cycloalkyl wherein each alkyl orcycloalkyl is optionally substituted with phenyl, OH, C₁₋₃alkoxy orNR₁₃R₁₄; or R₁₂ is phenyl or heterocycle, optionally substituted withone to three groups selected from C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(m)NR₁₀R₁₁, (CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁,

[0180] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0181] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0182] m is 1-4, n is 0-3 and p is 0-2; and

[0183] the pharmaceutically acceptable acid or salt derivatives thereof.

[0184] In another embodiment of the invention, there are providedcompounds of the formula (la) as described above, wherein:

[0185] X is NH or N—CH₃;

[0186] R_(a) is H, hydroxyC₁₋₂alkyl, 2-hydroxyethylaminomethyl,methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl,3-hydroxy-2-oxo-propyl, vinyl or C₃₋₅alkynyl substituted by C₁₋₃alkoxyor phenyl; and wherein R_(a) is attached at the 4- position;

[0187] R₁ and R₂ are the same or different and selected from: H,halogen, C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally partially orfully halogenated, NO₂, NR₁₃R₁₄;

[0188] R₃ is H, halogen, methoxy or methyl;

[0189] R₄ and R₅ together complete a fused ring of formula B;

[0190] R₈ is H, C₁₋₃alkyl optionally substituted with OH; or R₈ is(CH₂)₂₋₃NR₁₀R₁₁ or CO₂R₁₂;

[0191] R₉ is CN; or R₉ is methyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl, eachbeing optionally substituted with one or more C₅₋₇ cycloalkylidene,C₅₋₇cycloalkenyl, OH, CN, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀COR₁₂,NR₁₀S(O)_(p)R₁₂, CONR₁₀R₁₁, CO₂R₁₂, C(R₁₀)═NNR₁₀R₁₁ or heteroaryl;

[0192] or R₉ is aryl or heteroaryl optionally substituted with one tothree groups selected from C₁₋₃alkyl optionally substituted with phenyl,C₁₋₃alkoxy, halogen, amino or CONH₂;

[0193] or R₈ and R₉ together form a cyclopentene ring spiro-fused to a1,3 dioxolane group, said 1,3 dioxolane group being optionallysubstituted by C₁₋₃alkyl, C₁₋₃alkoxy, OH or (CH₂)_(n)NR₁₀R₁₁;

[0194] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, is OH, C₁₋₃alkoxy, C₁₋₃alkyl branched orunbranched, C₅₋₇cycloalkyl or phenyl, wherein said alkyl, cycloalkyl orphenyl are optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, NO₂,CO₂R₁₂, NR₁₃R₁₄, O(CH₂)₂₋₄NR₁₃R₁₄ or phenyl;

[0195] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy,OH, (CH₂)_(n)NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄;

[0196] R₁₂ is H, C₁₋₃alkyl or C₅₋₇cycloalkyl, each optionallysubstituted with phenyl, OH, C₁₋₃alkoxy or NR₁₃R₁₄; or R₁₂ is phenyl oris a saturated, 4- to 6-membered nitrogen-containing heterocycle, eachoptionally substituted with one to three groups selected from C₁₋₃alkyl,C₁₋₃alkoxy, halogen, (CH₂)_(m)NR₁₀R₁₁, (CH₂)_(n)CONR₁₀R₁₁ andO(CH₂)₂₋₄NR₁₀R₁₁;

[0197] R₁₃ and R₁₄ are each independently selected from H and C₁₋₃alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0198] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0199] In yet another embodiment of the present invention, there areprovided compounds of the formula (Ia) described immediately above,wherein:

[0200] R_(a) is H or hydroxymethyl;

[0201] R₁ and R₂ are the same or different and selected from: halogen,methyl optionally partially or fully halogenated, NO₂ and NH₂;

[0202] Is R₃ is H, chloro, fluoro, bromo or methoxy;

[0203] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, methoxy, C₁₋₃alkyl branched orunbranched or C₅₋₇cycloalkyl, wherein said alkyl or cycloalkyl areoptionally substituted with OH, NR₁₃R₁₄ or phenyl;

[0204] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₂ alkyl,NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄; and

[0205] R₁₂ is C₁₋₃alkyl optionally substituted with morpholino; or R₁₂is phenyl or is azetidinyl, pyrrolidinyl or piperidinyl, each optionallysubstituted with one to three groups selected from C₁₋₃alkyl, C₁₋₃alkoxyand halogen.

[0206] In still another subgeneric embodiment of the invention there areprovided compounds of the formula (Ia):

[0207] wherein:

[0208] X is NH, N—C₁₋₃alkyl, N-cyclopropyl, S or O;

[0209] R_(a) is H, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₁₀alkynyl, each ofwhich may be branched or cyclic; or R_(a) is aryl or heteroaryl;

[0210] wherein each R_(a) is independently optionally substituted withone or more C₁₋₆ alkoxy, halogen, OH, oxo, NR₁₀R₁₁, aryl or heteroaryleach aryl or heteroaryl being optionally substituted with one or moregroups selected from halogen, OH, C₁₋₃alkyl, C₁₋₃alkoxy,hydroxyC₁₋₃alkyl and (CH₂)_(m)NR₁₀R₁₁; and wherein R_(a) is attached atthe 4- or 5- position;

[0211] R₁ and R₂ are the same or different and selected from H, halogen,CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturated alkyl,C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranched acyl,C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₁₀R₁₁, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabove mentioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from oxo, OH, NR₁₀R₁₁, C₁₋₆ branched or unbranched alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl;

[0212] R₃ is H, halogen, OH, (CH₂)_(n)NR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂;C₁₋₃alkyl optionally substituted with OH, C₁₋₃ alkoxy optionallyhalogenated or C₁₋₃ alkylthio;

[0213] R₄ and R₅ together with the atoms to which they are attachedcomplete a fused ring system of the formulas A or B:

[0214] R₆ is C₁₋₃alkyl or H;

[0215] R₇ is C₁₋₆alkyl branched or unbranched or H;

[0216] R₈ is H, C₁₋₆alkyl branched or unbranched, saturated orunsaturated, optionally substituted with phenyl, OH or C₁₋₃alkoxy; or R₈is (CH₂)_(m)NR₁₀R₁₁, (CH₂)_(m)NR₁₀COR₁₂, (CH₂)_(n)CO₂R₁₂,(CH₂)_(n)CONR₁₀R₁₁ or R₈ is phenyl or heteroaryl, each being optionallysubstituted with C₁₋₃alkyl, C₁₋₃alkoxy, OH, —SO₃H or halogen;

[0217] R₉ is H; or R₉ is C₁₋₁₀alkyl branched or unbranched,C₃₋₁₀cycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl each being optionallysubstituted with one or more halogen, OH, oxo, CN, C₁₋₃alkoxy, NR₁₀R₁₁,NR₁₀COR₁₂, SR₁₂, CONR₁₀R₁₁, CO₂R₁₂, aryloxy, arylthio, aryl orheteroaryl; wherein each aryloxy, arylthio, aryl or heteroaryl isoptionally substituted with C₁₋₃alkyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₁₀R₁₁ or O(CH₂)₂₋₄NR₁₀R₁₁ ;

[0218] or R₉ is aryl or heteroaryl, wherein each aryl or heteroaryl isoptionally substituted with one to three groups selected from C₁₋₃alkyloptionally substituted with phenyl, C₁₋₃alkoxy, halogen,(CH₂)_(n)NR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂; (CH₂)_(n)CONR₁₀R₁₁ andO(CH₂)₂₋₄NR₁₀R₁₁ ;

[0219] or R₈ and R₉ together form a saturated or unsaturated 6 memberedaromatic or nonaromatic carbocyclic ring optionally substituted by oneor two OH, oxo or (CH₂)_(n)NR₁₀R₁₁;

[0220] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl and heteroaryl; whereinsaid alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl or heteroaryl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₂, NR₁₃R₁₄,O(CH₂)₂₋₄NR₁₃R₁₄, aryl or heteroaryl;

[0221] or R₁₀ and R₁₁ together form a 3-7 member alkylene chaincompleting a ring about the N atom to which they are attached; whereinsaid alkylene chain is optionally interrupted by O, S(O)_(p) and NR₁₃;and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₃R₁₄;

[0222] R₁₂ is H, C₁₋₆alkyl or C₃₋₈cycloalkyl wherein each alkyl orcycloalkyl is optionally substituted with phenyl, OH, C₁₋₃alkoxy orNR₁₃R₁₄; or R₁₂ is phenyl, optionally substituted with one to threegroups selected from C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(m)NR₁₀R₁₁,(CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0223] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl;

[0224] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂;

[0225] m is 1-4, n is 0-3 and p is 0-2; and

[0226] the pharmaceutically acceptable acid or salt derivatives thereof.

[0227] In another embodiment of the invention there are providedcompounds of the formula (Ia) as described immediately above, andwherein:

[0228] X is NH or N—CH₃;

[0229] R_(a) is H, hydroxyC₁₋₂alkyl, 2-hydroxyethylaminomethyl,methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl,3-hydroxy-2-oxo-propyl, vinyl or C₃₋₅alkynyl substituted by C₁₋₃alkoxyor phenyl; and wherein R_(a) is attached at the 4- position;

[0230] R₁ and R₂ are the same or different and selected from: halogen,C₁₋₃ alkyl, wherein the C₁₋₃ alkyl is optionally partially or fullyhalogenated, NO₂, NR₁₃R₁₄;

[0231] R₃ is H, halogen, methoxy or methyl;

[0232] R₄ and R₅ together complete a fused ring of formula B;

[0233] R₈ is H, C₁₋₃alkyl optionally substituted with OH; or R₈ is(CH₂)₂₋₃NR₁₀R₁₁ or CO₂R₁₂;

[0234] R₉ is methyl or C₂₋₄ alkenyl each being optionally substitutedwith one or more OH, CN, NR₁₀R₁₁, CONR₁₀R₁₁ or CO₂R₁₂;

[0235] or R₉ is heteroaryl optionally substituted with one to threegroups selected from C₁₋₃alkyl optionally substituted with phenyl,C₁₋₃alkoxy, halogen or (CH₂)_(n)NR₁₀R₁₁;

[0236] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₃alkyl branched orunbranched, optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy,CO₂R₁₂, NR₁₃R₁₄, O(CH₂)₂₋₄NR₁₃R₁₄ or phenyl;

[0237] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy or OH;

[0238] is R₁₂ is H or C₁₋₃alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₃R₁₄; R₁₃ and R₁₄ are each independently selected fromH and C₁₋₃alkyl optionally substituted with C₁₋₃alkoxy or OH;

[0239] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0240] In still a further embodiment of the invention there are providedcompounds of the formula (Ia) as described immediately above, andwherein:

[0241] R_(a) is H or hydroxymethyl;

[0242] R₁ and R₂ are the same or different and selected from: halogen,methyl optionally partially or fully halogenated, NO₂ and NH₂;

[0243] R₃ is H, chloro, fluoro, bromo or methoxy;

[0244] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, methoxy, Cl ₃alkyl branched orunbranched, optionally substituted with OH, NR₁₃R₁₄ or phenyl;

[0245] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₂ alkyl;and

[0246] R₁₂ is C₁₋₃alkyl optionally substituted with morpholino.

[0247] In another aspect of the invention, there are providedintermediate compounds of the formula(III) useful in the syntheticschemes and examples set forth below. In yet another aspect of theinvention are particular intermediate compounds of the formula(III),(representative examples shown Table 1 below) which possessphysiological activity.

[0248] In their broadest generic aspect, intermediate compoundsdescribed above are represented by the formula (III):

[0249] wherein:

[0250] Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocycle isoptionally substituted by one or more R₁, R₂ and R₃;

[0251] X is NH, N—C₁₋₃alkyl, N,cyclopropyl, S or O;

[0252] Y is NR₁₅, S or O;

[0253] R_(a) is H, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₁₀alkynyl, each ofwhich may be branched or cyclic; or R_(a) is aryl or heteroaryl;

[0254] wherein each R_(a) is independently optionally substituted withone or more C₁₋₃alkyl, C₁₋₆ alkoxy, halogen, OH, oxo, NR₁₀R₁₁, aryl orheteroaryl each aryl or heteroaryl being is optionally substituted withone or more groups selected from halogen, OH, C₁₋₃alkyl, C₁₋₃alkoxy,hydroxyC₁₋₃alkyl and (CH₂)_(m)NR₁₀R₁₁; and wherein R_(a) is attached atthe 4- or 5-position;

[0255] R₁ and R₂ are the same or different and selected from H, halogen,CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturated alkyl,C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranched acyl,C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₁₀R₁₁, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabovementioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from oxo, OH, NR₁₀R₁₁, C₁₋₆ branched or unbranched alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl;

[0256] R₃ is H, halogen, OH, (CH₂)_(n)NR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂;C₁₋₃alkyl optionally substituted with OH, C₁₋₃ alkoxy optionallyhalogenated or C₁₋₃ alkylthio;

[0257] R₄ and R₅ together with the atoms to which they are attachedcomplete a fused ring system of the formula C:

[0258] R₆ is C₁₋₃alkyl or H;

[0259] R₇ is C₁₋₆alkyl branched or unbranched or H;

[0260] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl and heteroaryl; whereinsaid alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl or heteroaryl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₂, NR₁₃R₁₄,O(CH₂)₂₋₄NR₁₃R₁₄, aryl or heteroaryl;

[0261] or R₁₀ and R₁₁ together form a 3-7 member alkylene chaincompleting a ring about the N atom to which they are attached; whereinsaid alkylene chain is optionally interrupted by O, S(O)_(p) and NR₁₃;and wherein said ring is optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₃R₁₄;

[0262] R₁₂ is H, C₁₋₆alkyl or C₃₋₈cycloalkyl wherein each alkyl orcycloalkyl is optionally substituted with phenyl, OH, C₁₋₃alkoxy orNR₁₃R₁₄; or R₁₂ is phenyl, optionally substituted with one to threegroups selected from C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(m)NR₁₀R₁₁,(CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁;

[0263] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with alkoxy, OH or phenyl;

[0264] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; and

[0265] m is 1-4, n is 0-3 and p is 0-2.

[0266] One embodiment of the compounds of formula(III) are thosewherein:

[0267] Ar₁ is

[0268] a) a cycloalkyl group selected from cyclopropyl, cyclobutyl,cyclopentanyl, cyclohexanyl, cycloheptanyl;

[0269] b) a cycloalkenyl group selected from cyclopentenyl,cyclohexenyl, cycloheptenyl;

[0270] c) phenyl, naphthyl; indanyl, indenyl, dihydronaphthyl,tetrahydronaphthyl, fluorenyl;

[0271] d) heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl,benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl, or afused heteroaryl selected from cyclopentenopyridine,cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; or

[0272] e) a heterocycle selected from: pyrrolinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, piperazinyl and indolinyl;

[0273] wherein each of the above Ar₁ are optionally substituted by oneor more R₁, R₂ and R₃ as hereinabove defined;

[0274] R_(a) is H, C₁₋₆alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, phenyl orheteroaryl selected from: pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, furyl, thiazolyl andthienyl; each R_(a) being optionally substituted with one or morephenyl, halogen, C₁₋₃alkyl, C₁₋₃ alkoxy, OH, oxo, or NR₁₀R₁₁; whereinR_(a) is at the 4- position;

[0275] R₃ is H, halogen, methyl, methoxy, hydroxymethyl or OH;

[0276] R₆ is C₁₋₃alkyl or H;

[0277] R₇ is C₁₋₆alkyl branched or unbranched or H;

[0278] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branched orunbranched, C₃₋₈cycloalkyl, benzyl and phenyl;

[0279] wherein said alkyl, cycloalkyl or phenyl are optionallysubstituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy, CO₂R₁₂, NR₁₃R₁₄,O(CH₂)₂₋₄NR₁₃R₁₄ or phenyl;

[0280] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy, OH or —(CH₂)_(n)NR₁₃R₁₄;

[0281] R₁₂ is H or C₁₋₆alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₃R₁₄;

[0282] R₁₃ and R₁₄ are each independently selected from H and C₁₋₆ alkyloptionally substituted with C₁₋₃alkoxy, OH or phenyl; and

[0283] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0284] Another embodiment of the compounds of the formula(III) are thosedescribed immediately above, and wherein:

[0285] Ar₁ is phenyl, or pyridyl;

[0286] X is NH or N—CH₃;

[0287] Y is NH and

[0288] R_(a) is H, hydroxyC₁₋₂alkyl, 2-hydroxyethylaminomethyl,methoxybenzylaminomethyl, pyridinyl optionally halogenated, phenyl,3-hydroxy-2-oxo-propyl, vinyl or C₃₋₅alkynyl substituted by C₁₋₃alkoxyor phenyl;

[0289] R₁ and R₂ are the same or different and selected from: halogen,C₁₋₃ alkyl, wherein the C₁₋₃ alkyl are optionally partially or fullyhalogenated, NO₂, NR₁₃R₁₄;

[0290] R₃ is H, halogen, methoxy or methyl;

[0291] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, C₁₋₃alkoxy, C₁₋₃alkyl branched orunbranched, optionally substituted with OH, C₁₋₃alkoxy, C₁₋₃acyloxy,CO₂R₁₂, NR₁₃R₁₄, O(CH₂)₂₋₄NR₁₃R₁₄ or phenyl;

[0292] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₃ alkyl,C₁₋₃alkoxy or OH;

[0293] R₁₂ is H or C₁₋₃alkyl optionally substituted with phenyl, OH,C₁₋₃alkoxy or NR₁₃R₁₄;

[0294] R₁₃ and R₁₄ are each independently selected from H and C₁₋₃alkyloptionally substituted with C₁₋₃alkoxy or OH;

[0295] or R₁₃ and R₁₄ together form a chain completing a ring, saidchain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂.

[0296] In yet another embodiment of the compounds of formula(III) arethose described immediately above, and wherein:

[0297] Ar₁ is phenyl;

[0298] R_(a) is H or hydroxymethyl;

[0299] R₁ and R₂ are the same or different and selected from: halogen,methyl optionally partially or fully halogenated, NO₂ and NH₂;

[0300] R₃ is H, chloro, fluoro, bromo or methoxy;

[0301] R₁₀ and R₁₁ may be the same or different and are eachindependently selected from H, OH, methoxy, C₁₋₃alkyl branched orunbranched, optionally substituted with OH, NR₁₃R₁₄ or phenyl;

[0302] or R₁₀ and R₁₁ together form morpholino, pyrrolidinyl,piperazinyl or piperidinyl each optionally substituted by C₁₋₂ alkyl;and

[0303] R₁₂ is C₁₋₃alkyl optionally substituted with morpholino.

[0304] In a further embodiment of the invention, there are provided thefollowing compounds of the fomulas (I) and (Ia):

[0305]2-(2,6-Dichlorophenylamino)-6,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0306] 2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;

[0307]2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0308]2-(2,6-Dichlorophenylamino)-7-methyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0309] 2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-acetic acidethyl ester;

[0310] 3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylicacid methyl ester;

[0311]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-hydroxyethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0312]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylicacid methyl ester;

[0313]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0314] 3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylicacid methyl ester;

[0315]3-[2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-yl]propionicacid ethyl ester

[0316]N-Benzyl-N-methyl-2-[(2,6-dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-yl]acetamide;

[0317]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-morpholin-4-ylethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0318]2-(2-Chloro-6-methylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0319]2-(4-Bromo-2-dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0320]3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-N-methoxy-N-methylacrylamide;

[0321]2-(2-Chloro-6-nitrophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0322]N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylamide;

[0323]3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylicacid 4-morpholine amide;

[0324]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-[3-(4-morpholino)propyl]-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0325]2-(2,6-Dichlorophenylamino)-4-hydroxymethyl-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0326]2-(2,6-Dimethylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0327]2-(2-Ethyl-6-methylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0328]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(3-phenylaminopropyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0329]2-(2,6-Dichlorophenylamino-6-{3-[4-(2-diethylaminoethoxy)-phenylamino]propyl}-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0330]2-(2-Bromo-6-chloro-4-fluorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0331]2-(2,6-Dichlorophenylamino)-4-(2-hydroxyethylaminomethyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0332]2-(2,6-Dichlorophenylamino)-4-(4-methoxybenzylaminomethyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0333]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0334]2-(2,6-Dichlorophenylamino)-4-(2,6-difluoropyridin-3yl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0335] 2-(2,6-Dichlorophenylamino)-4-(3-methylphenyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0336]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylicacid 2-(4-moropholino)ethyl ester;

[0337]2-(2,6-Dichlorophenylamino)-4-(3-hydroxy-2-oxo-propyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0338]N-4-(2-Diethylaminoethoxy)phenyl-3-[2-(2,6-dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylamide;

[0339] 3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-N-methyl acrylamide;

[0340] 9-Hydroxy-2-(2,6-dichlorophenylamino)-3,5,6,7,8,9-hexahydro-imidazo[4,5-i]phenanthridin-4-one;

[0341]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-hydroxypropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0342]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(2-phenylethenyl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0343]2-(2-Amino-6-chlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0344]2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-4-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0345]2-(2,6-Dichlorophenylamino)-4-(3-methoxypropyn-1-yl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0346]2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-4-(5-phenylpent-1-ynyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0347]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;

[0348]2-(2,6-Dichlorophenylamino)-1-methyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0349]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-morpholin-4-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0350]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-[2-(2-hydroxyethyl)aminoethyl]-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0351]3-[2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylonitrile;

[0352]2-(2-Chloro-6-methylphenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0353]2-(2,6-Dichlorophenylamino)-1-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;

[0354]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(3-hydroxypropyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0355]2-(2,6-Dichlorophenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0356]2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0357]2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0358]7-(3-Aminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0359]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-pyrrolidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0360]7-(3-Benzylmethylaminopropen-1-yl)2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0361]2-(2,6-Dichloro-4-methoxyphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0362]2-(2,6-Dichloro-4-methoxyphenylamino)-1,6-dimethyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;

[0363]2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0364]2-(2,6-Dimethylphenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0365]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(4-methylpiperazin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0366]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-piperidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0367]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[ethyl(2-hydroxyethyl)amino]propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0368]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-hydroxypyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0369]7-(3-Dibutylaminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0370]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[(2-methoxyethyl)methylamino]propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0371]7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,6-dimethylphenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0372]2-(2,6-Dichlorophenylamino)-7-{3-[(2-diethylaminoethyl)methylamino]-propen-1-yl}-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0373] 7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,4,6-trichlorophenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0374]2-(2,6-Dichlorophenylamino)-6-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

[0375]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0376]7-[3-(2S-Aminomethylpyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0377]1-{3-[2-(2,6-Ddichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-L-proline carboxamide

[0378]1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxamide

[0379]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(methylhydrazonomethyl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0380]7-[3-(3-Aminopyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0381]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-acetamidopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0382]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-dimethylaminopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinotin-9-one

[0383]1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-2-carboxamide

[0384]7-[3-(3-Aminomethylpiperidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0385] 1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxylicacid diethylamide

[0386]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-ethynyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0387]1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-3-methylurea

[0388] Cyclohexane carboxylic acid{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0389]2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

[0390] N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}methanesulfonamide

[0391]3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenylurea

[0392]1-Cyclohexyl-3-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-urea

[0393]N-{13-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}benzenesulfonamide

[0394]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-ethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0395]N-{13-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-guanidine

[0396] Piperidine-3-carboxylic acid{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0397] L-Proline{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0398] D-Proline{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0399]3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-benzamide

[0400] L-Azetidine-2-carboxylic acid{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0401] Piperidine-2-carboxylic acid{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide;

[0402]2-(2-Chloro-6-methylphenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0403]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[(3-dimethylamino-propyl)methylamino]-propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0404]2-(2,6-Dichlorophenylamino)-7-[3-(2-diethylaminoethylthio)-propen-1-yl]-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0405]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-dimethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0406]7-(3-N-Cyclohexyl-N-methylaminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0407]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-N-isopropyl-N-methylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;and

[0408] the pharmacuetically acceptable derivatives thereof.

[0409] In yet still a further embodiment of the invention, there areprovided the following compounds of the fomulas (I) and (Ia):

[0410]2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one;

[0411]2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0412]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-hydroxyethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0413]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylicacid methyl ester;

[0414]3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylicacid methyl ester;

[0415]2-(2-Chloro-6-methylphenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0416] 3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-N-methoxy-N-methylacrylamide;

[0417]2-(2-Chloro-6-nitrophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0418]N-Benzyl-3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylamide;

[0419]3-[2-(2,6-Dichlorophenylamino)-1-methyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylicacid 4-morpholine amide;

[0420]2-(2,6-Dichlorophenylamino)-4-hydroxymethyl-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0421]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0422]2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-6-carboxylicacid 2-(4-moropholino)ethyl ester;

[0423]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-hydroxypropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0424]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;

[0425]2-(2,6-Dichlorophenylamino)-1-methyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0426]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-morpholin-4-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0427]3-[2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylonitrile;

[0428]2-(2-Chloro-6-methylphenylamino)-1,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one;

[0429]2-(2,6-Dichlorophenylamino)-1-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one;

[0430]2-(2,6-Dichlorophenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0431]2-(2-Chloro-6-methylphenylamino)-7-(3-hydroxypropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0432]2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0433]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-pyrrolidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0434]2-(2,6-Dichlorophenylamino)-7-(3-diethylaminopropen-1-yl)-1-methyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0435]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(4-methylpiperazin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0436]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-piperidin-1-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0437]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[ethyl(2-hydroxyethyl)amino]propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0438]7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,6-dimethylphenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0439]2-(2,6-Dichlorophenylamino)-7-{3-[(2-diethylaminoethyl)methylamino]-propen-1-yl}-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0440]7-(3-Diethylaminopropen-1-yl)-1,6-dimethyl-2-(2,4,6-trichlorophenylamino)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0441]2-(2,6-Dichlorophenylamino)-6-methyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

[0442] 2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(2-pyrrolidin-1-ylmethylpyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0443]7-[3-(2S-Aminomethylpyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0444]1-{3-[2-(2,6-Ddichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-L-prolinecarboxamide

[0445]1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxamide

[0446]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(methylhydrazonomethyl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0447]7-[3-(3-Aminopyrrolidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0448]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-acetamidopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0449]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-[3-(3-dimethylaminopyrrolidin-1-yl)-propen-1-yl]-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0450]1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-2-carboxamide

[0451]7-[3-(3-Aminomethylpiperidin-1-yl)-propen-1-yl]-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0452]1-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-piperidine-3-carboxylicacid diethylamide

[0453]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-ethynyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0454]1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-3-methylurea

[0455] Cyclohexane carboxylic acid{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0456]2-(2,6-Dichlorophenylamino)-1-methyl-7-phenyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

[0457]N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}methanesulfonamide

[0458]3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenylurea

[0459]1-Cyclohexyl-3-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-urea

[0460]N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}benzenesulfonamide

[0461]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-ethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one

[0462]N-{3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-guanidine

[0463] Piperidine-3 -carboxylic acid {3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0464] L-Proline{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0465] D-Proline{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0466]3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-benzamide

[0467] L-Azetidine-2-carboxylic acid{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide

[0468] Piperidine-2-carboxylic acid{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}amide;

[0469]2-(2-Chloro-6-methylphenylamino)-7-(3-diethylaminopropen-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0470]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-{3-[(3-dimethylamino-propyl)methylamino]-propen-1-yl}-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0471]2-(2,6-Dichlorophenylamino)-7-[3-(2-diethylaminoethylthio)-propen-1-yl]-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0472]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-dimethylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0473]7-(3-N-Cyclohexyl-N-methylaminopropen-1-yl)-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;

[0474]2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-N-isopropyl-N-methylaminopropen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one;and

[0475] the pharmacuetically acceptable derivatives thereof.

[0476] Any compounds of this invention containing one or more asymmetriccarbon atoms may occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be in the R or Sconfiguration, or a combination of configurations.

[0477] Some of the compounds of the invention can exist in more than onetautomeric form. The invention includes all such tautomers.

[0478] The compounds of the invention are only those which arecontemplated to be ‘chemically stable’ as will be appreciated by thoseskilled in the art. For example, a compound which would have a ‘danglingvalency’, or a ‘carbanion’ are not compounds contemplated by theinvention.

[0479] All terms as used herein in this specification, unless otherwisestated, shall be understood in their ordinary meaning as known in theart. For example, “C₁₋₆alkoxy” is a C₁₋₆alkyl with a terminal oxygen,such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl,alkylene or alkynyl groups shall be understood as being branched orunbranched unless otherwise specified. Other more specific definitionsare as follows:

[0480] The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine.

[0481] The term “heteroaryl” refers to a stable 5-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicaromatic heterocycle radical. Each heterocycle consists of carbon atomsand from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. Theheterocycle may be attached by any atom of the cycle, which results inthe creation of a stable structure. Example “heteroaryl” radicalsinclude, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl,quinazolinyl, 2,4-dioxo-quinazolinyl, imidazo[4,5-c]pyridinyl andindazolyl, or a fused heteroaryl such as cyclopentenopyridine,cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine,cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine,cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline,cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole,cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole,cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole,cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene;

[0482] The term “heterocycle” refers to a stable 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicheterocycle radical which may be either saturated or unsaturated, and isnon-aromatic. Each heterocycle consists of carbon atoms and from I to 4heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle maybe attached by any atom of the cycle, which results in the creation of astable structure. Example “heterocycle” radicals include azetidinyl,pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl,piperazinyl,indolinyl, 2,3-dihydrobenzimidazolyl and2,3-dihydro-1H-imidazo[4,5-c] pyridinyl. As used herein and throughoutthis specification, the terms “nitrogen” and “sulfur” and theirrespective elements symbols include any oxidized form of nitrogen andsulfur and the quatemized form of any basic nitrogen.

[0483] The term “aryl” shall be understood to mean a 6-10 memberedaromatic carbocycle, “aryl” includes, for example, phenyl and naphthyl;other terms comprising “aryl” will have the same definition for the arylcomponent, examples of these moieties include: arylalkyl, aryloxy orarylthio.

[0484] The term “carbocycle” shall be understood to mean a 3-10 memberedaromatic or nonaromatic cyclic carbon chain. Examples of nonaromaticcarbocycles include cyclopropyl, cyclobutyl, cyclopentyl and the like.Examples of aromatic carbocycles include the “aryl” compounds asdescribed hereinabove.

[0485] The term “acyl” shall be understood to mean an R—(C═O)— moietywherein R is an alkyl. Examples of R can be a C₁₋₁₀alkyl, saturated orunsaturated, branched or unbranched, or R can be “aryl” as definedhereinabove. “Acyloxy” shall be understood to mean an R-CO₂— groupwherein R is as defined in this paragraph.

[0486] The invention includes pharmaceutically acceptable derivatives ofcompounds of the invention. A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester of a compound ofthis invention, or any other compound which, upon administration to apatient, is capable of providing (directly or indirectly) a compound ofthis invention, a pharmacologically active metabolite orpharmacologically active residue thereof.

[0487] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acidsinclude hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

[0488] In addition, the compounds of this invention include prodrugs ofcompounds of the invention. Prodrugs include those compounds that, uponsimple chemical transformation, are modified to produce a compound ofthe invention. Simple chemical transformations include hydrolysis,oxidation and reduction, enzymatically, metabolically or otherwise.Specifically, when a prodrug of this invention is administered to apatient, the prodrug may be transformed into a compound of theinvention, thereby imparting the desired pharmacological effect.

[0489] General Synthetic Methods

[0490] The compounds of the invention may be prepared by the methodsdescribed below. Optimum reaction conditions and reaction times may varydepending on the particular reactants used. Unless otherwise specified,solvents, temperatures, pressures and other reaction conditions may bereadily selected by one of ordinary skill in the art. Specificprocedures are provided in the Synthetic Examples section. Typically,reaction progress may be monitered by thin layer chromatography (TLC) ifdesired. If desired, intermediates and products may be purified bychromatography on silica gel and/or recrystallization. Startingmaterials and reagents are either commercially available or may beprepared by one skilled in the art using methods described in thechemical literature.

[0491] A general procedure (Method A) that may be used to synthesizecompounds of formula 10 (I) is illustrated in Scheme I.

[0492] An optionally substituted diamine II is reacted with an arylisothiocyanate in a suitable solvent such as EtOAc, DMF or THF at aboutambient to reflux temperature for about 3 to 24 hr to provide thioureaIII. Alternately, one can begin with a salt of II and react with an arylisothiocyanate in pyridine or in a neutral solvent such as THF in thepresence of a suitable base such as triethylamine. Reaction of thethiourea with a suitable activating agent such as1,3-dicyclohexylcarbodiimide (DCC) or mercuric oxide in a suitablesolvent such as THF or DMF at about ambient to reflux temperatureprovides I or a precursor to I which may undergo further chemicaltransformation to obtain the desired compound. If desired, one mayperform the two steps without isolating the thiourea, by adding DCC ormercuric oxide to the reaction of II and the aryl isothiocyanate.

[0493] One may also prepare benzothiazoles (formula I, X═S) by Method A,starting with the analogous aminothiophenol. Preferably, one may alsouse Method B illustrated in Scheme II and described below.

[0494] In this method, an appropriately substituted aniline is reactedwith an aryl isothiocyanate as in Method A to provide thiourea V.Reaction of V under cyclizing conditions, such as in the presence ofbromine in a suitable solvent such as chloroform at about refluxtemperature, provides I (X═S) or a precursor to I.

[0495] The starting diamine (II) in Method A may be prepared byreduction of a nitroaniline, for example under hydrogen atmosphere inthe presence of a suitable catalyst such as palladium on carbon in asuitable solvent, such as EtOAc or HOAc.

[0496] One procedure (Method C) for preparing starting nitroanilines isillustrated in Scheme III and described below.

[0497] In Method C, 2,6-dichloro-3-nitrobenzonitrile (VI) is reactedwith an amine in a suitable solvent, such as EtOH, THF or EtOAc,optionally in a pressure flask and at about 0 to 80° C., to provide VII.Reaction of VII with keto-ester VIII in the presence of a suitable base,such as K₂CO₃, potassium t-butoxide or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable solvent, such asDMF or DMSO at about ambient temperature provides IX. Hydrolysis andcyclization of IX to provide X is accomplished by reaction with aqueousacid, for example a mixture of acetic acid, sulfuric acid and water atabout reflux temperature. Reduction of nitroaniline X, in a suitablesolvent, preferably acetic acid and/or trifluoroacetic acid, asdescribed above, provides XI.

[0498] In a variation of Method C, one may reduce intermediate IX asdescribed above, to the corresponding diamine and form the benzimidazoleby Method A prior to formation of the isoquinolinone.

[0499] A procedure for introducing R_(A) into compounds of formula (I)is illustrated in Scheme IV.

[0500] Intermediate XII (prepared as described in Scheme III forpreparation of IX, followed by reduction) is reacted with bromine in asuitable solvent, such as chloroform at ambient temperature to provideXIII. Intermediate XIII is converted to XIV according to Method A.Cross-coupling chemistry can be used to introduce carbon in place ofbromine. For example, reaction with vinyl tributyltin in the presence ofa suitable catalyst, such as (PPh₃)₂PdCl₂, in a suitable solvent, suchas 1-methyl-2-pyrrolidinone (NMP) at about 100° C., provides XV.Alternately, reaction with a terminal alkyne in the presence of asuitable catalyst, such as (PPh₃)₂PdCl₂, and CuI, and a suitable base,such as triethylamine in a solvent such as THF at about ambienttemperature provides an alkyne as R_(a). Other R_(a) may be obtained bytransformation of these R_(a) by methods known to those skilled in theart. Several of these transformations are exemplified below.

[0501] A method for preparing compounds of the invention in which R₄ andR₅ represent ring B, which is based on the procedure described in J.Heterocyclic Chem., 1970, 7, 615, is shown in Scheme V.

[0502] Intermediate XVI (prepared according to Method A or Method B) isreacted with a reducing agent such as sodium borohydride, in a suitablesolvent, such as THF or dioxane, at about 0° C. to ambient temperature,to give intermediate XVII, in which one carbonyl of the imide has beenreduced selectively. Treatment of XVII with a strong acid, such assulfuric acid, at ambient temperature, causes rearrangement to theisoquinolone XVIII. It will be appreciated that this method is mostsuitable for compounds where R₆, R₇, R₈ and R₉ are all the same group,preferably methyl. In a variation of this method, the reduction of theimide and rearrangement to the isoquinolone can be carried out prior toforming the benzimidazole ring.

[0503] Functional groups at R₈ or R₉ on compounds of formula (I) orintermediates prepared as illustrated in the Schemes above may also betransformed by methods known to those skilled in the art to prepareadditional compounds of the invention. Several of these transformationsare also exemplified below.

[0504] Methods of Therapeutic Use

[0505] The compounds of the invention are useful in inhibiting theactivity of src-family kinases and PDGFR kinase. In doing so, thecompounds are effective in blocking disease processes mediated by thesekinases. For example, by inhibiting p56 lck, the compounds blockdownstream signaling events following T cell activation by antigen.Activation of antigen-specific T cells is necessary for the inductionand progression of diseases, including autoimmune diseases, allergicdiseases and transplant rejection (J. H. Hanke et al., Inflamm. Res.,1995, 44, 357). Therefore the compounds of the invention are useful fortreating such diseases. These include but are not limited to rheumatoidarthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease,ulcerative colitis, psoriasis, graft versus host disease, systemic lupuserythematosus, insulin-dependent diabetes mellitus and asthma.

[0506] In view of their inhibitory effect on src-family kinases andPDGFR kinase, the compounds of the invention are useful in treatingcancer. For example, the compounds of the invention are useful intreating src-dependent tumors, such as in mammary carcinoma, coloncarcinoma, melanoma and sarcoma, and are also useful in treatingPDGF-dependent tumors, such as ovarian cancer, prostate cancer andglioblastoma. In view of their inhibitory effect on src kinase, thecompounds of the invention are also useful in treating conditionsinvolving cerebral ischemia, for example, in reducing brain damagefollowing a stroke.

[0507] By inhibiting p60src, compounds of the invention may also beuseful in treating osteoporosis, Paget's disease, bone inflammation andjoint inflammation. By inhibiting PDGFR kinase, compounds of theinvention may also be useful in treating fibrotic diseases, restenosisand atherosclerosis. By inhibiting lyn kinase, the compounds of theinvention may also be useful in enhancing or potentiating theeffectiveness of radiation therapy.

[0508] For therapeutic use, the compounds of the invention may beadministered in any conventional dosage form in any conventional manner.Routes of administration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, rectally, topically or byinhalation. The preferred modes of administration are oral andintravenous. Compositions comprising the compounds of the invention foreach of the aforementioned routes of administration will be apparent tothe skilled artisan. For example, one embodiment of the inventionprovides for pharmaceutical compositions including a pharmaceuticallyeffective amount of the compounds according to the invention. Suchpharmaceutical compositions will include pharmaceutically acceptablecarriers and adjuvants as further described below.

[0509] The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutic compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formula (I) (w/w) or a combinationthereof. The optimum percentage (w/w) of a compound of formula(I) mayvary and is within the purview of those skilled in the art.Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

[0510] As mentioned above, dosage forms of the compounds of thisinvention include pharmaceutically acceptable carriers and adjuvantsknown to those of ordinary skill in the art. These carriers andadjuvants include, for example, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1 -1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

SYNTHETIC EXAMPLES Example 1

[0511] Synthesis of2-(2,6-Dichlorophenylamino)-6,6-dimethyl-1H,6H-imidazo[4,5-h]isoquinoline-7,9-dione.

[0512] 4,4-Dimethyl-7-nitro-2H,4H-isoquinoline- 1,3-dione, prepared asdescribed in U.S. Pat. No. 4,666,923 (1987), (1.0 g, 4.5 mmol) inmethanol (50 mL) was hydrogenated over 10% Pd/C (30 mg) at 50 psi for1.5 h. The catalyst was removed by filtration and the solvent removed togive 8-amino-4,4-dimethyl-2H,4H-isoquinoline-1,3-dione (0.90 g, 98%).

[0513] The above amine (1.5 g, 7.35 mmol) was stirred in aceticanhydride (9 mL) at room 15 temperature for 3 h, then poured on to ice.The precipitate was filtered, washed with water and dried to give7-acetamido-4,4-dimethyl-2H,4H-isoquinoline-1,3-dione (1.55 g, 86%)

[0514] The above amide was converted to7-acetamido-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-1,3-dione asdescribed in U.S. Pat. No. 4176184 (1979).

[0515] 7-Acetamido-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-1,3-dione(4.0 g, 13.7 mmol) was added to 90% H₂SO₄ and heated at 70° C. for 8 h.The cooled mixture was poured onto ice. The precipitate was collected,dissolved in ethyl acetate, washed with water, dried and evaporated togive 7-amino-4,4-dimethyl-8-nitro-2H,4H-isoquinoline- 1,3-dione (3.38 g,99%), mp 259-263° C.; MS (CI) 250 (MH+).

[0516] A solution of the above amine (1.5 g, 6.0 mmol) in methanol (50mL) was hydrogenated over platinum oxide (30 mg) at 50 psi for 1.25 h.The mixture was filtered through diatomaceous earth and evaporated toprovide 7,8-diamino-4,4-dimethyl-2H,4H-isoquinoline-1,3-dione. (1.31 g,100%). MS (CI) 220 (MH+).

[0517] As described in Method A, 2,6-dichlorophenylisothiocyanate (1.16g, 5.7 mmol) was added to a suspension of7,8-diamino-4,4-dimethyl-2H,4H-isoquinoline- 1,3-dione (1.31 g, 6.0mmol) in ethyl acetate (40 mL) and the mixture stirred overnight. Thesolid was filtered and dried to yield the thiourea (1.55 g, 61%).mp >300° C.; MS (CI) 423, 425 (MH+). A solution of the thiourea (2.23 g,5.28 mmol) in THF (50 mL) and dicyclohexylcarbodiimide (1.11 g, 5.4mmol) was heated under reflux with stirring for 4 h. The cooled solutionwas stirred overnight, filtered, and the crystals washed with CH₂Cl₂ togive the title compound (1.20 g). The filtrate was evaporated andtriturated with CH₂Cl₂ to give more product (0.7 g, 93% combined yield),mp 290-292° C.; MS (EI) 388, 390 (M+).

Example 2

[0518] Synthesis of2-(2,6-Dichlorophenylamino)-6,6-dimethyl-7,8-dihydro-1H,6H-imidazo[4,5-h]isoquinoline-9-one.

[0519] To a solution of the product of Example 1 (90 mg, 0.23 mmol) inTHF (5 mL) was added NaBH₄ (90 mg, 2.3 mmol) followed by water (4drops). The reaction mixture was stirred at ambient temperature for 1 h.Subsequently, IN HCl (5 mL) was added dropwise and the reaction mixturewas stirred an additional 15 minutes, neutralized with NaHCO₃ andextracted with EtOAc. The extract was washed with brine, dried andevaporated yielding the alcohol2-(2,6-dichlorophenylamino)-6,6-dimethyl-7-hydroxy-7,8-dihydro-1H,6H-imidazo[4,5-h]isoquinoline-9-one(90 mg 99%). This intermediate was used immediately due to itsinstability. It was characterized as the methyl ether, which wasprepared by dissolving the product in MeOH/HCl and stirring for severalhours. After evaporation, the residue was partitioned between EtOAc/aqNaHCO₃. The organic phase was washed with brine, dried and evaporated tothe methyl ether derivative, mp 278-280° C.(dec); MS (ES) 405 (MH+).

[0520] The alcohol from above (100 mg, 0.26 mmol) was dissolved in TFA(2 mL) and this solution was subsequently added to a solution of sodiumtristrifluoroacetoxyborohydride (generated in-situ from 160 mg, 4.2 mmolof sodium borohydride and 3 mL TFA) at 0° C. The reaction mixture wasstirred at ambient temperature for 4 h, the solvent was evaporated, theresidue was triturated with water and the resultant mixture wasneutralized with NaHCO₃ and filtered yielding the title compound (85 mg,92%). This product was purified by flash chromatography on SiO₂ using 4%MeOH/CH₂Cl₂ as eluant and recrystallization from EtOAc, mp 287-290° C.;MS (CI) 375 (MH⁺).

Example 3a

[0521] Synthesis of2-(2,6-Dichlorophenylamino)-6,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0522]2-(2,6-Dichlorophenylamino)-6,6-dimethyl-7-hydroxy-7,8-dihydro-1H,6H-imidazo[4,5-h]isoquinoline-9-one(from Example 2) (45 mg, 0.11 mmol) was suspended in conc. H₂SO₄ (1 mL)and the resultant mixture was stirred at ambient temperature for 15 min.The solution was poured over ice, neutralized with NaHCO₃ and filtered.The filtrate was triturated with water (10 mL) and centrifuged. Theliquid was decanted, and the residual solid was triturated with methanoland centrifuged. The supernatant was decanted and the residue dried togive the title compound (35 mg, 84%). Mp >300° C.; MS (ES) 373 (MH⁺).

Example 3b

[0523] Synthesis of2-(2,6-Dichlorophenylamino)-6,7-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one(Method C).

[0524] A 500 mL pressure flask was charged with2,6-dichloro-3-nitrobenzonitrile (30.0 g, 138 mmol) and a 5.1M solutionof ammonia in EtOH (170 mL). The flask was sealed and heated in an oilbath at 80° C. with stirring for 1.5 h. The cooled solution wasfiltered, the crystals washed with water and dried to yield2-amino-6-chloro-3-nitrobenzonitrile (18.4 g, 68%), mp 181-184° C.; MS(ES⁻) 196, 198 (M-H⁻).

[0525] To a solution of 2-amino-6-chloro-3-nitrobenzonitrile (1.97 g, 10mmol) and ethyl 2-methylacetoacetate (3.6 g, 25 mmol) in DMF (10 mL) wasadded finely powdered K₂CO₃, and the mixture stirred vigorously for 24h. The deep red mixture was diluted with EtOAc and washed in turn with 2M HCl, water and brine. The residue after evaporation was purified byflash chromatography in hexane/EtOAc 3:1 to yield2-(3-amino-2-cyano-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethyl esteras an oil (1.39 g, 46%), MS (NH₃ CI) 323 (M+NH₄ ⁺), 293 (M+NH₄−NO⁺).

[0526] The ester from above (1.39 g, 4.56 mmol) was added to a mixtureof acetic acid (20 mL), H₂SO₄ (3 mL) and water (2 mL), and the solutionheated at 100° C. for 3 h. The cooled solution was diluted with water(30 mL), the precipitate was collected, washed with water and MeOH anddried to give 8-amino-3,4-dimethyl-7-nitro-2H-isoquinolin-1-one (0.76 g,72%). mp >300° C.

[0527] A solution of the amino isoquinolin-l-one from above (0.20 g,0.86 mmol) in trifluoroacetic acid (11 mL) and acetic acid (7 mL) washydrogenated over 10% palladium on carbon (21 mg) at 50 psi for 2 h. Thesolution was filtered through diatomaceous earth, washing with aceticacid, and the filtrate evaporated to give7,8-diamino-3,4-dimethyl-2H-isoquinolin-1-one ditrifluoroacetate salt(310 mg, 83%).

[0528] A suspension of the diamino isoquinolin- 1-one ditrifluoroacetatesalt from above (1.15 g, 2.67 mmol) and 2,6-dichlorophenylisothiocyanate(0.60 g, 2.93 mmol) in pyridine (16 mL) was stirred for 18 h at roomtemperature (Method A). The solution was diluted with toluene andevaporated, and remaining pyridine removed with a toluene azeotrope. Theresidue was triturated with EtOAc to give the thiourea (1.17 g). Aportion of this material (0.50 g, 1.23 mmol) anddicyclohexylcarbodiimide (0.375 g, 1.84 mmol) were heated together inDMF under argon at 80° C. for 4 h. The cooled solution was evaporatedand triturated first with cold MeOH, then with boiling MeOH, to leavethe title compound as a light tan solid, (0.309 g, 73%), identical withthe sample obtained in Example 3a.

Example 4

[0529] Synthesis of2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0530] A solution of 2,6-dichloro-3-nitrobenzonitrile (98.7 g, 0.455mol) in EtOAc (910 mL) was cooled to 5° C. 40% Aqueous methylamine (79.5mL, 1.14 mol) was added with vigorous mechanical stirring, keeping thetemperature at 10-15° C. After addition was complete, stirring wascontinued for 3 h at the same temperature. More methylamine (16 mL, 0.23mol) was added, and the mixture stirred for a further 1.5 h at roomtemperature. Water (300 mL) was added, followed by hexane (450 mL). Themixture was stirred for 15 min, filtered, and the solid washed withwater and MeOH, to give 6-chloro-2-methylamino-3-nitrobenzonitrile (80.3g, 83%), mp 167-170° C.

[0531] To a stirred solution of potassium t-butoxide (24.3 g, 206 mmol)in DMSO (500 mL) was added ethyl 2-methylacetoacetate (34.3 g, 233mmol), dropwise over 5 min. The temperature rose to 30° C.6-Chloro-2-methylamino-3-nitrobenzonitrile (43.6 g, 190 mmol) was addedin portions over 15 min. The temperature rose to 40° C. The solution wasstirred for 1 h with no external heating or cooling. The mixture waspoured into 10% NH₄Cl (500 mL), and extracted with EtOAc (2×500 mL). Thecombined extracts were washed with water (2×250 mL) and brine, andevaporated. MeOH (200 mL) was added to the residue and stirred for 1.5h. The yellow solid was filtered, washed with cold MeOH (25 mL) anddried to give2-(2-cyano-3-methylamino-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethylester (36.2 g, 60%), mp 87-91 ° C.

[0532] A solution of the above ester (10.5 g, 32.5 mmol) in EtOAc (130mL) was hydrogenated over 10% palladium on carbon (0.5 g) at 50 psi for24 h. The catalyst was removed by filtration through diatomaceous earth,and the filtrate was evaporated. A mixture of EtOAc/hexane (1:1, 10 mL)was added to the residue and the resulting mixture was stirred for 0.5h. The crystals were filtered and washed with hexane to give2-(4-amino-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethylester (7.74 g, 81%), mp 118-123° C.

[0533] A solution of the amino ester from above (7.7 g, 26.6 mmol) and2,6-dichlorophenylisothiocyanate (5.43 g, 26.6 mmol) in THF (150 mL) wasstirred at room temperature for 5 h. Mercuric oxide (6.34 g, 29.3 mmol)was then added in one portion, and stirring continued overnight. Themixture was filtered through diatomaceous earth, washing well with THF.The filtrate was evaporated, and the residue triturated with ether togive2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimiazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester as an off-white solid (7.7 g, 63%).

[0534] To a stirred mixture of conc. H₂SO₄ (40 mL), HOAc (40 mL) andwater (40 mL) at 60° C. was added2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimiazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester (7.4 g, 16 mmol) in one portion. The solution washeated at 100° C. for 2.5 h, then stirred overnight at room temperature.The reaction mixture was poured onto ice, and neutralized with conc.NH₄OH, with ice cooling. The precipitate was filtered and washed wellwith water. The solid was slurried in MeOH, stirred well, filtered,washed with MeOH until washings were colorless, and dried. The titlecompound was obtained as a grey solid (5.48 g, 88%), mp >300° C.; MS(NH₃ CI) 387, 389 (MH+).

Example 5

[0535] Synthesis of2-(2,6-Dichlorophenylamino)-6,6-dimethyl-6H-thiazolo[4,5-h]isoquinoline-7,9-dione(Method B).

[0536] To a suspension of7-amino-4,4-dimethyl-2H,4H-isoquinoline-1,3-dione (204 mg, 1 mmol) inEtOAc (25 mL) was added 2,6-dichlorophenylisothiocyanate (223 mg, 1.1mmol) in three portions, and the mixture was stirred overnight. Thesolid was filtered and dried to yield the thiourea (380 mg, 93%), mp142-144° C.; MS (CI) 408(MH⁺). To a suspension of the thiourea (140 mg,0.34 mmol) in CHCl₃ (20 mL) was added Br₂ (60 mg, 0.37 mmol) in CHCl₃ (2mL) dropwise. The solution was heated to reflux for 1 h. The solvent wasevaporated and the residue triturated with saturated NaHCO₃ (50 mL). Thesolid was filtered, washed with water, and dried, to yield the titlecompound (114 mg, 82%), mp >300° C.; MS (CI) 406(MH+).

Example 6

[0537] Synthesis of2-(2,6-Dichlorophenylamino)-6,7-dimethyl-8H-thiazolo[4,5-h]isoquinoline-9-one(Method B).

[0538] To a solution of7-nitro-4,4-dimethyl-2H,4H-isoquinoline-1,3-dione from Example 1 (1.0 g,4.3 mmol) in THF (50 mL) was added NaBH₄ (330 mg, 8.7 mmol) followed bywater (10 drops). The reaction mixture was stirred at room temperaturefor 2.5 h, cooled in an ice bath and treated with IN HCl until a paleyellow color was maintained. After 10 min. the reaction mixture wasneutralized with saturated NaHCO₃ and extracted with EtOAc. The extractwas washed with brine, dried and evaporated to the alcohol, which wasimmediately taken up in conc. H₂SO₄ (8 mL). This mixture was stirreduntil completely dissolved (10 min.), poured over ice, neutralized with10% NH₄0H, allowed to stand several hours, filtered and dried to yield3,4-dimethyl-7-nitro-isoquinoline-1-one (780 mg, 83%). MS (CI) 219(MH⁺).

[0539] A solution of 3,4-dimethyl-7-nitro-isoquinoline-1-one (750 mg,3.4 mmol) in MeOH (250 mL) was hydrogenated over Pd/C (25 mg) at 60 psifor 24 h. The reaction mixture was filtered through diatomaceous earth,washing well with MeOH. Evaporation of the filtrate provided the amine(554 mg, 85%) which was immediately dissolved in EtOAc (60 mL) andtreated with 2,6-dichlorophenylisothiocyanate (663 mg, 3.3 mmol). Themixture was stirred at ambient temperature for 48 h, refluxed for 4 hand stirred at ambient temperature an additional 72 h. The thiourea wasfiltered and washed with EtOAc (850 mg, 74%). mp 220° C. (dec). Aportion of the thiourea (490 mg, 1.25 mmol) was suspended in CHCl₃ (50mL) and treated with a solution of Br₂ (200 mg, 1.25 mmol) in CHCl₃ (5mL), and the resulting mixture was refluxed for 1 h. The solvent wasevaporated, the residue was suspended in a saturated solution of NaHSO₃,filtered, then treated analogously with a saturated solution of NaHCO₃.Purification by silica column chromatography (0 to 5% MeOH in CH₂Cl₂eluant) yielded the title compound (281 mg, 58%), mp >300° C., MS (CI)390 (MH⁺).

Example 7

[0540] Synthesis of2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-morpholin-4-yl-2-oxoethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0541] To a solution of2-(2,6-dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-ylacetic acid (prepared using Methods C and A) (1.0 g, 2.3 mmol) in DMF (7mL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) (0.82 g, 2.6 mmol) and morpholine (0.24 mL, 2.8mmol), and the mixture stirred 18 h at room temperature. Ice water wasadded, the precipitate collected, washed with water and dried to givethe title compound, 0.97 g, 84%, mp >300° C.; MS (ES) 500, 502 (MH+).

Example 8

[0542] Synthesis of2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-morpholin-4-yl-ethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0543] A stirred suspension of the product of Example 7 (85 mg, 0.17mmol) in THF (9 mL) was heated to reflux and borane-methylsulfide (0.09mL, 0.9 mmol) added. Stirring was continued for 3.5 h at reflux andovernight at room temperature. 6M HCl was added and the solution stirredfor 2 h. The solution was applied to a Varian SCX column, washed withMeOH/CH₂Cl₂ 50:50, then the product eluted with MeOH/CH₂Cl₂/NH₄OH50:50:1. The product was further purified on a silica column elutingwith CH₂Cl₂/MeOH 98:2 to give the title compound 32 mg, 39%, mp 285-290°C.; MS (ES) 486, 488 (MH+).

Example 9

[0544] Synthesis of2-(2,6-Dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-ylacetic acid ethyl ester.

[0545] Prepared from2-(2,6-dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-ylacetic acid by refluxing in ethanol and H₂SO₄. Mp 280-285° C. (dec);MS(CI) 459, 461 (MH+).

Example 10

[0546] Synthesis2-(2,6-Dichlorophenylamino)-1,7-dimethyl-6-(2-hydroxyethyl)-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0547] To a stirred solution of the product of Example 9 (25 mg, 0.05mmol), in THF (2 mL), under nitrogen, was added a solution of lithiumaluminum hydride (1M in THF, 0.25 mL, 0.25 mmol). The mixture wasstirred for 30min at room temperature. Ethyl acetate was added, followedby water, and then acidified with 1N HCl. The whole mixture was appliedto a Varian SCX cartridge, and washed in turn with 1N HCl, water,acetone, MeOH, and MeOH/CH₂Cl₂ (1:1). The product was then eluted withMeOH/CH₂Cl₂/NH₄OH (49:49:2). Evaporation of the eluent gave the titlecompound (15 mg, 72%). Mp >300° C.; MS(ES) 417, 419 (MH+).

Example 11

[0548] Synthesis of2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde.

[0549] The method described below is useful for preparing intermediatecompounds such as 11, which possess an aldehyde moiety at the7-position.

[0550] To a suspension of the product from Example 4 (521 mg, 1.3 mmol)in dioxane (30 mL) was added selenium dioxide (430 mg, 3.9 mmol) and themixture was heated at 100° C. for 5 h. The reaction was then cooled toroom temperature, filtered through diatomaceous earth with 10%MeOH-CH₂Cl₂ and then concentrated in vacuo. The crude material wastriturated with CH₂Cl₂ to provide the title compound (476 mg, 92%),mp: >300° C.; MS (CI) 401, 403 (MH+).

Example 12

[0551] Synthesis of3-12-[2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-acrylicacid methyl ester.

[0552] To a suspension of the product of Example 11 (329 mg, 0.82 mmol)in THF (5 mL) was added sequentially, trimethyl phosphonoacetate (164mg, 0.90 mmol), lithium hydroxide monohydrate (76 mg, 1.8 mmol) andwater (0.9 mL). The blood red solution was stirred for 2 h, quenchedwith water, and the resulting solid was collected and dried in vacuo.Column chromatography (5% MeOH-CH₂Cl₂) provided the title compound (300mg, 80%), mp >300° C.; MS (ES) 457, 459 (MH+).

Example 13

[0553] Synthesis of3-[2-(2,6-Dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propionicacid methyl ester.

[0554] To a solution of the product of Example 12 (30 mg, 0.06 mmol) inEtOH (3 mL) and AcOH (4 mL) in a Parr reactor was added PtO₂ (2 mg,0.007 mmol). The Parr reactor was charged with 50 psi of H₂ and shakenfor 12 h. The crude reaction was filtered through diatomaceous earthwith EtOH and concentrated in vacuo. Column chromatography (2%MeOH-CH₂Cl₂) provided the title compound (9 mg, 30%), mp 268° C.(dec);MS(ES) 459, 461 (MH+).

Example 14

[0555] Synthesis of2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-hydroxy-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one.

[0556] A suspension of the product of Example 12 (100 mg, 0.22 mmol) inTHF (7 mL) was cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M inTHF, 0.44 mmol) was added dropwise. The bright red solution was warmedto 0° C. for 15 minutes, then lithium aluminum hydride (1M in THF, 2.6mmol) was added and the orange solution was warmed to room temperaturefor 0.5 h. The mixture was cooled to 0° C., quenched with saturatedammonium chloride and extracted with ethyl acetate. Columnchromatography (3-6% MeOH-CH₂Cl₂) provided the title compound (32 mg,34%), mp 298-300° C.; MS(ES) 429, 431 (MH+).

Example 15

[0557] Synthesis of2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0558] To a suspension of the product of Example 11 (100 mg, 0.25 mmol)in THF (5 mL) was added trimethylsilylmethyl magnesium chloride (2 mL, 2mmol) at −78° C. The reaction was warmed to room temperature for 1 h,then cooled to 0° C. and quenched with water and extracted with ethylacetate to provide the silyl alcohol (85 mg, 70%). The crude silylalcohol was suspended in CH₂Cl₂ and cooled to 0° C. Borontrifluorideetherate (42 μL, 0.32 mmol) was added and the slurry was warmed to roomtemperature for 1 h. The reaction was quenched with water, and theCH₂Cl₂ was removed in vacuo. Collection of the resulting solid followedby CH₂Cl₂ trituration provided the title compound (17 mg, 61%), mp >300°C.; MS(Es) 399, 401(MH+).

Example 16

[0559] Synthesis of2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(1-hydroxyprop-2-en-1-yl)-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one.

[0560] A suspension of2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde(2) (100 mg, 0.25 mmol) in THF (3 ml) was cooled to −78° C.Vinylmagnesium bromide (1M in THF, 2.0 mmol) was added dropwise, and thebrown suspension was warmed gradually to −10° C. over 2 h. The solutionwas quenched with saturated ammonium chloride and extracted with ethylacetate, and concentrated in vacuo to provide the title compound, whichwas used in the next step without purification, mp 235-236° C., MS (ES)429 (MH+).

Example 17

[0561] Synthesis of2-(2,6-Dichlorophenylamino)-7-(1-acetoxyprop-3-en-1-yl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one.

[0562] To a solution of the product of Example 16 (106 mg, 0.25 mmol) inTHF (1 ml) was added acetic anhydride (1 ml). Triethylamine (35 μL, 0.25mmol) was added, and the reaction was stirred for 14 h, thenconcentrated in vacuo. Column chromatography (2% MeOH—CH₂Cl₂) providedthe title compound (85 mg, 79%), mp 169-171° C.; MS (ES) 471 (MH+).

Example 18

[0563] Synthesis of2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-morpholin-4-yl-propen-1-yl)-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one.

[0564] Tris(dibenzylideneacetone) dipalladium(0) (1.8 mg, 0.002 mmol)and triphenylphosphine (1.6 mg, 0.006 mmol) were stirred in THF (0.5 ml)for 20 min under inert atmosphere until the red solution turned yellow.To this solution was added sequentially, the product of Example 17 (20mg, 0.04 mmol) in THF (0.5 ml), triethylamine (17 μL, 0.12 mmol) andmorpholine (11 μL, 0.12 mmol). The solution was stirred 14 h, thenconcentrated to an oil. Column chromatography (10% MeOH-CH₂Cl₂) providedthe title compound (10 mg, 50%), mp 175-177° C.; MS (ES) 498 (MH+).

Example 19

[0565] Synthesis of7-Benzylaminomethyl-2-(2,6-dichlorophenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one.

[0566] To a suspension of the product of Example 11 (50 mg, 0.12 mmol)in THF (4 mL) was lo added benzylamine (54 mg, 0.50 mmol). The reactionwas stirred for 12 h, then concentrated in vacuo. The crude imine wassuspended in MeOH (2 mL), sodium borohydride (21 mg, 0.55 mmol) wasadded, and the reaction was stirred for 3 h. The reaction was quenchedwith water, and the resulting solid was collected and dried to providethe title compound (11 mg, 39%), mp 231-234° C.; MS (ES) 492(MH+).

Example 20

[0567] Synthesis of2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-oxazol-5-yl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one.

[0568] A suspension of the product of Example 11 (40 mg, 0.10 mmol),tosylmethyl isocyanide (21 mg, 0.11 mmol) and K₂CO₃ in methanol (2 mL)was heated to 40° C. for 90 min. The mixture was diluted with water (3mL) and the solid collected by filtration to obtain the title compound(26 mg, 60%), mp >300° C.; MS (ES) 440, 442(MH+).

Example 21

[0569] Synthesis of2-(2,6-Dichlorophenylamino)-1,6-dimethyl-7-(3-methyl-3H-imidazol-4-yl)-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one.

[0570] A suspension of the product of Example 11 (50 mg, 0.13 mmol) andmethylamine (2M in THF, 2 mL, 4 mmol) in dry THF (2 mL) was stirred atroom temperature for 12 h. The THF was evaporated and the resultingimine was mixed with tosylmethyl isocyanide (27 mg, 0.14 mmol), K₂CO₃(31 mg, 0.23 mmol) and dry DMSO (2 mL). This suspension was stirred forfive days at room temperature. Water (5 mL) was added and theprecipitate collected by filtration. Flash chromatography in CH₂Cl₂/MeOH(98:2) gave the title compound (8 mg, 14%), mp >300° C.; MS(ES) 453, 455(MH+).

Example 22

[0571] Synthesis of2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-4-vinyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0572] To a solution of2-(4-amino-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyric acid ethylester from Example 4 (9.02 g, 31.2 mmol) in CHCl₃ (90 mL) was addedbromine (4.98 g, 31.2 mmol) dropwise at ambient temperature. After theaddition of bromine, the reaction mixture was diluted with ethyl acetate(800 mL). This solution was washed successively with sat. NaHCO₃solution and brine and dried. The residue after evaporation was purifiedby flash chromatography in hexanes/EtOAc 2:1 to yield2-(4-amino-5-bromo-2-cyano-3-methylaminophenyl)-2-methyl-3-oxobutyricacid ethyl ester as an oil (6.06 g, 53%).

[0573] To a solution of the above ester (3.32 g, 9.02 mmol) in1,4-dioxane (45 mL) was added 2,6-dichlorophenylisothiocyanate (2.02 g,9.92 mmol) and mercuric oxide (2.54 g, 11.7 mmol) under nitrogenatmosphere. The resulting mixture was stirred and heated at 95° C.overnight. The reaction mixture was cooled to room temperature andfiltered though a short pad of diatomaceous earth and SiO₂. The filtratewas concentrated and the residue was purified by flash chromatography inhexanes/EtOAc 2:1 to yield2-[8-bromo-4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimiazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester as a brown solid (3.44 g, 71%).

[0574] A mixture of the above bromo ester (600 mg, 1.11 mmol),(PPh₃)₂PdCl₂ (78 mg, 0.11 mmmol) and tributyl(vinyl)tin (0.49 mL, 1.67mmol) in NMP (4 mL) was degassed and heated at 100° C. for 3 days underargon. The mixture was concentrated and the residue was purified byflash chromatography in hexanes/EtOAc 3:1 to yield2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-8-vinyl-3H-benzimiazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester as an oil (530 mg, 98%).

[0575] A solution of the above keto ester (66 mg, 0.14 mmol) in amixture of H₂SO₄ (0.6 mL), acetic acid (0.6 mL) and water (0.6 mL) washeated at 100° C. for 2 h. The resulting mixture was cooled to roomtemperature and diluted with water (10 mL). The solution was adjusted topH 8 with 10% NaOH solution. The precipitated brown solid was filteredand purified by flash chromatography in CH₂Cl₂/MeOH 30:1 to yield thetitle compound (15 mg, 27%), mp decomp. above 250° C.; MS (CI) 413(MH+).

Example 23

[0576] Synthesis of2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinoline-4-carbaldehyde.

[0577] A solution of2-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-8-vinyl-3H-benzimiazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester (see Example 22) (538 mg, 1.11 mmol) in THF (30 mL) wastreated with 2.5% OSO₄ solution in tBuOH (3.0 mL), NaIO₄ (712 mg, 3.33mmol) and water (3 mL). After stirring for 1.5 h at room temperature,the mixture was diluted with EtOAc. The organic solution was washed withbrine, dried and concentrated. The residue was purified by flashchromatography in hexanes/EtOAc 4:1 to yield2-[4-cyano-2-(2,6-dichlorophenylamino)-8-formyl-3-methyl-3H-benzimiazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester as an oil 345 mg, 64%).

[0578] A solution of the above aldehyde (35 mg, 0.07 mmol) in a mixtureof H₂SO₄ (0.6 mL), acetic acid (0.6 mL) and water (0.6 mL) was heated at100° C. for 1.5 h and cooled to room temperature. The resulting mixturewas diluted water (10 mL) and the pH adjusted to 7 with ammoniumhydroxide solution. The precipitated orange powder was filtered to givethe title compound as an orange solid (18 mg, 60%).

Example 24

[0579] Synthesis of2-(2,6-Dichlorophenylamino)-4-(2-hydroxyethylaminomethyl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0580] A suspension of the product of Example 23 (30 mg, 0.07 mmol) inMeOH (5 mL) was treated with ethanolamine (44 μL, 0.72 mmol) and NaBH₃CN(14 mg, 0.22 mmol), and stirred at room temperature for 16 h. Theresulting mixture was concentrated and the residue was diluted withwater. The precipitated solid was filtered to give the title compound(12 mg, 36%). mp decomp. above 250° C.; MS (CI) 460 (MH+).

Example 25

[0581] Synthesis of2-(2,6-Dichlorophenylamino)-4-(3-methoxypropyn-1-yl)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinoline-9-one.

[0582] A mixture of2-[8-bromo-4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester (see Example 22) (50 mg, 0.09 mmol), methyl propargylether (16 μL, 0.19 mmol), (PPh₃)₂PdCl₂ (6.5 mg, 0.009 mmol) and Cul (3.5mg, 0.02 mmol) in Et₃N (1 mL) and THF(1 mL) was stirred at roomtemperature for 5 days under argon. The resulting mixture wasconcentrated and the residue was purified by flash chromatography inhexanes/EtOAc 3:1 to give2-[4-cyano-2-(2,6-dichlorophenylamino)-8-(4-methoxypropyn-1-yl)-3-methyl-3H-benzimidazol-5-yl]-2-methyl-3-oxobutyricacid ethyl ester as an oil (30 mg, 61%).

[0583] A solution of the above ketoester (29 mg, 0.006 mmol) in amixture of H₂SO₄ (0.4 mL), acetic acid (0.4 mL) and water (0.4 mL) washeated at 100° C. for 2 h. The resulting mixture was cooled to roomtemperature and diluted with water (10 mL). The pH of this solution wasadjusted to 8 with 10% NaOH solution. The precipitated solid wasfiltered to give the title compound (17 mg, 68%), mp decomp. above 250°C.; MS(CI) 455 (MH+).

Example 26

[0584] Synthesis of2-(2,6-Dichlorophenylamino)-3,5-dihydro-imidazo[4,5-i]phenanthridin-4-one.

[0585] To a solution of N-(t-butoxycarbonyl)aniline (2.0 g, 10.35 mmol)in dry THF (50 mL) at 78° C., a solution of t-BuLi (2.7M in pentane, 26mL, 25.88 mmol) was added dropwise over 30 min. The resulting yellowsolution was warmed to −20° C. and stirred at this temperature for 2.5h. n-BU3SnCt (4.2 mL, 15.52 mmol) in dry THF (10 mL) was added over 20min, and the solution stirred at −20° C. for 2 h, then at roomtemperature for 12 h.

[0586] The reaction mixture was poured into NaHCO₃ solution andextracted with ether. The extract was washed with water, brine, anddried over MgSO₄. The solvent was evaporated and the resulting oilpurified by flash chromatography in hexanes/ether (20: 1) to give2-tributylstannylphenylcarbamic acid t-butyl ester (2.42 g, 54%).

[0587] Tin(II) chloride (46.67 g, 206.84 mmol) was added portionwise toa solution of 2-bromo-5-nitro benzoic acid (12.71 g, 49.9 mmol) in dryethanol (200 mL). The mixture was heated at 70° C. for 45 min, thenethanol was evaporated. The residue was cooled to 0° C., and aceticanhydride (43 mL) and pyridine (26 mL) were added. The solution wasstirred at room temperature for 14 h and evaporated. The residue waspartitioned between aq. 2M HCl and ethyl acetate (400 mL). The organicphase was washed with brine and dried over MgSO₄. The residue fromevaporation was crystallized from water to give5-acetylamino-2-bromobenzoic acid (12.4 g, 96%).

[0588] 5-Acetylamino-2-bromobenzoic acid (6.81 g, 26.39 mmol) was addedportionwise to fuming nitric acid (90%, 11 mL) at 0° C. (as described byH. Goldstin, G. Preitner. Helv. Chim. Acta 1944, 27, 888). The ice bathwas removed and the solution stirred at room temperature for 1.5 h, thenpoured into ice water. 3-Acetylamino-6-bromo-2-nitro-benzoic acid wascollected by filtration (5.07 g, 63%).

[0589] To a solution of 3-acetylamino-6-bromo-2-nitro-benzoic acid (3.86g, 14.96 mmol) in dry THF (42 mL) and dry methanol (18 mL) was added asolution of (trimethylsilyl)diazomethane in hexane (2M, 24 mL, 48 mmol).The solution was stirred at room temperature for 3 h and evaporated. Theresidue was purified by flash chromatography in hexanes/ethyl acetate(6:1) to give 3-acetylamino-6-bromo-2-nitrobenzoic acid methyl ester(2.45 g, 52%).

[0590] A solution of 3-acetylamino-6-bromo-2-nitrobenzoic acid methylester (1.3 g, 4.11 mmol) and Pd(PPh₃)₄ (0.31 g, 0.27 mmol) in drytoluene (15 mL) was stirred at room temperature for 10 min. To thisorange solution was added a solution of 2-tributylstannylphenylcarbamicacid t-butyl ester (2.10 g, 4.94 mmol) in dry toluene (10 mL) and themixture was heated to reflux for 14 h, during which time a precipitateformed. 8-Acetamido-7-nitro-6-oxo-5,6-dihydro-phenanthridin-6-one wascollected by filtration as an off-white solid (1.07 g, 88%).

[0591] A suspension of8-acetamido-7-nitro-6-oxo-5,6-dihydro-phenanthridin-6-one (770 mg, 2.66mmol) and NaOMe (25% w/w solution in MeOH, 3.5 mL, 6.64 mmol) in drymethanol (15 mL) was heated to reflux for 3 h. The methanol wasevaporated and the residue triturated with water and filtered to yield8-amino-7-nitro-5H-phenanthridin-6-one (500 mg, 74%).

[0592] A mixture of 8-amino-7-nitro-5H-phenanthridin-6-one (412 mg, 1.62mmol), Pd/C (10 wt %, 234 mg) in TFA was hydrogenated at 50 psi for 50min. The catalyst was filtered through a plug of diatomaceous earth andrinsed with ethanol. The solvent was evaporated to obtain7,8-diamino-5H-phenanthridin-6-one trifluoroacetate salt (520 mg, 71%).

[0593] To a solution of 7,8-diamino-5H-phenanthridin-6-onetrifluoroacetate salt (200 mg, 0.44 mmol) in pyridine (3 mL) was added2,6-dichlorophenylisothiocyanate (93 mg, 0.46 mmol). The suspension wasstirred at room temperature for 14 h. The pyridine was evaporated usinga toluene azeotrope. The residue was triturated with ethanol to obtainthe thiourea (150 mg, 79%). A mixture of thiourea (146 mg, 0.34 mmol)and dicyclohexylcarbodiimide (83 mg, 40.80 mmol) in dry THF (2 mL) anddry DMF (0.9 mL) was heated to 80° C. for 8 h. The solvent was removedunder high vacuum and the residue triturated with hot ethanol to givethe title compound (82 mg, 61%), mp >300° C.; MS(CI) 395, 397(MH+).

Example 27

[0594] Synthesis of2-(2,6-Dichlorophenylamino)-3-methyl-5,6,7,8-tetrahydro-3H-1,3,5-triaza-dicyclopenta[a,f]naphthalen-4-one.

[0595] A mixture of 6-chloro-2-methylamino-3-nitrobenzonitrile (200 mg,0.95 mmol) (Example 4), ethyl 2-oxocyclopentanecarboxylate (177 mg, 1.13mmol) and K₂CO₃ (287 mg, 2.07 mmol) in DMF (5 mL) was stirred at roomtemperature for 60 h. The mixture was diluted with sat. NH₄Cl solutionand extracted with ether. The ethereal layer was washed with water andbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by chromatography on silica (hexanes: EtOAc=3:1) to give ethyl1-(2-cyano-3-methylamino-4-nitrophenyl)-2-oxo-cyclopentanecarboxylate(127 mg, 40%) as a yellow solid.

[0596] To a solution of the above compound (100 mg, 0.30 mmol) in aceticacid (1 mL) was added a solution of tin (II) chloride dihydrate (681 mg,3.0 mmol) in c. HCl (0.5 mL) at room temperature. The resulting mixturewas stirred at room temperature for 2 h and quenched with sat. NaHCO₃solution. The pH of the mixture was adjusted to 8 with NaHCO₃. Theproduct was extracted into EtOAc and the organic layer was washed withwater and brine, dried (Na₂SO₄), and concentrated to give ethyl1-(4-amino-2-cyano-3-methylaminophenyl)-2-oxo-cyclopentanecarboxylate(76 mg, 84%) as a yellow oil.

[0597] A mixture of the above diamine (140 mg, 0.46 mmol),2,6-dichlorophenyl isothiocyanate (104 mg, 0.51 mmol) and HgO (110 mg,0.51 mmol) in THF (5 mL) was refluxed for 8 h. The cooled mixture wasfiltered through diatomaceous earth and concentrated. The residue wasdiluted with EtOAc, washed with water and brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by chromatography onsilica in hexanes/EtOAc, (1:1) to give ethyl1-[4-cyano-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazol-5-yl]-2-oxo-cyclopentanecarboxylate(200 mg, 92%) as a light yellow solid.

[0598] A solution of the above benzimidazole (195 mg, 0.41 mmol) in a1:1:1 mixture of water, acetic acid and H₂SO₄ (1.5 mL) was heated at 100° C. for 3 h. The reaction mixture was cooled and diluted with water.The precipitate was collected and washed with water. The collectedyellow solid was purified by chromatography on SiO₂ in CH₂Cl₂ /MeOH(20:1) to give the title compound (70 mg, 43%) as a light yellow solid.Mp >300° C. (dec.), MS (CI) m/z 399 (M⁺+H).

Example 28

[0599] Synthesis of7-(3-Aminopropen-1-yl)-2-(2,6-dichlorophenylamino)-i,6-dimethyl-1,8-dihydro-imidazo[4,5-h]-isoquinolin-9-one.

[0600] A suspension of tris(dibenzylideneacetone) dipalladium(0) (185mg, 0.25 mmol) and triphenylphosphine (320 mg, 1.2 mmol) in THF (40 mL)was stirred for 20 min under N₂. A solution of the product from Example17 (1.88 g, 4.0 mmol) in THF (5 mL) was added and the mixture stirredfor 20 min. Sodium azide (280 mg, 4.4 mmol) and water (4.0mL) were addedand the reaction was heated at 60° C. for 3 h. The solution was cooledto rt and triphenylphosphine (1.0 g, 3.8 mmol) was added. After stirringfor 45 min., ammonium hydroxide (4 mL) was added and stirring continuedovernight. The resulting solution was dried over MgSO₄, thenconcentrated to an oil. Column chromatography on silica eluting withCH₂Cl₂/MeOH (90:10 increasing to 50:50) provided the title compound (1.2g, 70%), mp >300° C.; MS (ES) 428 (MH+).

Example 29

[0601] Synthesis of1-{3-[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-propenyl}-3-phenylurea.

[0602] A solution of the product of Example 28 (50 mg, 0.12 mmol) andphenyl isocyanate (17 mg, 0.13 mmol) in DMF (2 mL) was heated at 60° C.for 10 h. The resulting precipitate was filtered, triturated withMeOH/CH₂Cl₂ (90:10), and dried to provide the title compound (57 mg,89%) mp >290° C.; MS (ES) 547 (MH+).

Other Examples

[0603] Using methods analogous to those described above, the followingcompounds of this invention (Tables 1-3) were prepared: TABLE 1Compounds of Formula I with R₄, R₅ = C

Example X R₁ R₂ R₃ R_(a) R₆ R₇ m.p. ° C. 30 NH Me Cl H H Me Me >300 31NH Cl Cl Cl H Me Me >275 32 NH Me Me H H Me Me >300

[0604] TABLE 2 Compounds of Formula I with R₄, R₅ = A

Example X R₁ R₂ R₃ R₁ R₆ R₇ m.p. ° C. 33 NH Cl Cl H H H H 172-178

[0605] TABLE 3 Compounds of Formula I with R₄, R₅ = B

Ex: X R₁ R₂ R₃ R_(a) R₈ R₉ m.p. ° C. 34 S Cl Cl H H Me Me >300 35 NH HCl H H Me Me >300 36 NH Cl Cl Cl H Me Me >250 37 NH Br Br Br H MeMe >250 38 NH Cl Me H H Me Me >250 39 NH Cl Cl H H H n-Pr >250 40 NH ClCl H H CO₂Et Me 265 41 NH Cl Cl H H Me CHO >300 42 NH Cl Cl H H CH₂CO₂EtMe 292-296 43 NH Cl Cl H H H Me >300 44 NH Cl Cl H H Me CH₂OH >300 45 NHCl Cl OMe H Me Me >300 46 NH Cl Cl H H CH₂CO₂H Me >250 47 NMe Cl Cl H HMe CH₂NH(CH₂)₂NEt₂ 194-196 48 NMe Cl Cl H H Me CH₂OH >280 49 NMe Cl Cl HH Me CH₂NHMe 263-265 50 NMe Cl Cl H H Me CH₂NH(CH₂)₂OMe 215-218 51 NMeCl Cl H H Me CH₂(4-morpholinyl) 292-295 52 NMe Cl Cl H H CH₂CO₂Et Me280-285 53 NMe Cl Cl H H CH₂C(O)NHEt Me >300 54 NMe Cl Cl H HCH₂C(O)NMe₂ Me >300 55 NMe Cl Cl H H CH₂C(O)NH—CH₂Ph Me >300 NEt₂ 56 NMeCl Cl H H CH₂C(O)NH—(CH₂)₂ Me 298-302 NEt₂ 57 NMe Cl Cl H H CH₂C(O)NH—Me >300 (CH₂)₂Ph 58 NMe Cl Cl H H CH₂C(O)(4Me- Me >300 piperazin-1-yl)59 NMe Cl Cl H H CH₂C(O)NH(CH₂)₃ Me 267.5-270   NEt₂ 60 NMe Cl Cl H HCH₂CH₂OH Me >300 61 NMe Cl Cl H H CH₂C(O)(4- Me >300 morpholinyl) 62 NMeCl Cl H H CH₂C(O)NH(CH₂)₂ Me 277-283 (4-morpholinyl) 63 NMe Cl Cl H H HCH═CHCO₂Me >300 64 NMe Cl Cl H H CH₂C(O)NH— Me >262 (CH₂)₂NEt₂ 65 NMe ClCl H H (CH₂)₂CO₂H Me 295-305 66 NMe Cl Cl H H (CH₂)₂CO₂Et Me 268-273 67NH Cl Cl H H CH₂C(O)NMe₂ Me >300 68 NMe Br Br H H Me Me 238-240 69 NMeCl Cl H H (CH₂)₂OC(O)Me Me >275 70 NMe Cl Cl H H CH₂C(O)NHCH₂ Me >300(pyridin-2-yl) 71 NMe Cl Cl H H (CH₂)₂(4- Me 285-290 morpholinyl) 72 NMeCl Cl H H (CH₂)₂NHEt Me 253-262 73 NMe Cl Cl H H CH₂C(O)NH₂ Me >300 74NMe Cl Cl H H H CH═CHC(O)N(OMe)Me >300 75 NMe Cl CF₃ H H Me Me 226-22876 NMe Cl NO₂ H H Me Me 278-280 77 NMe Cl Cl H C(O)Me Me Me >300 78 NMeCl Cl H H H CH═CHC(O)NHCH₂Ph >300 79 NMe Cl Cl H C(OH)Me Me Me 308-31180 NMe Cl Cl H H CH₂CH(OMe)₂ Me 247-248 81 NMe Cl Cl H H HCH═CHC(O)(4-morpholinyl) >300 82 NMe Cl Cl H H (CH₂)3(4- Me 277-282morpholinyl) 83 NMe Cl Cl H CH₂OH Me Me >300 84 NMe Me Me H H Me Me315-318 85 NMe Me Et H H Me Me 289-291 86 NMe Cl Br F H Me Me 317-319 87NMe Cl Cl H CH₂NH- Me Me 247-250 CH₂₋(4- OMe)Ph 88 NMe Cl Cl H (3-Me)PhMe Me 220-223 89 NMe Cl Cl H CH₂C(O)— Me Me 285 CH₂OH 90 NMe Cl Cl H HMe CH═CHC(O)NH-[4-O(CH₂)₂NEt₂]Ph >300 91 NMe Cl Cl H H HCH═CHC(O)NHMe >300 92 NMe Cl NH₂ H H Me Me 300-302 93 NMe Cl Cl H(CH₂)₃OH Me Me 208-210 94 NMe Cl Cl H H H CH═CH₂ 259-261 95 NMe Cl Cl HH Me CH═CHCH₂-4-morpholinyl 175-177 96 NMe Cl Cl H H Me CH═CHCN >300 97NMe Cl Me H H H Me >300 98 NMe Cl Cl H H H 5-oxazolyl >300 99 NMe Cl ClH H (CH₂)₃OH Me 265-275 100 NMe Cl Cl H H H CH═CHCH₂OH 285 101 NMe Cl MeH H H CH═CHCH₂OH 264-266 102 NMe Cl Cl H H Me CH═CHCH₂NEt₂ 150-153 103NMe Cl Cl H H Me CH═CHCN 280 104 NMe Cl Cl H H MeCH═CHCH₂-(1-pyrrolidinyl) 170-173 105 NMe Cl Cl H H MeCH═CHCH₂N(Me)(CH₂Ph) 134-136 106 NMe Cl Cl OMe H Me Me >300 107 NMe ClCl OMe H Me 5-oxazolyl >300 108 NMe Cl Cl OCF₃ H Me Me >300 109 NMe ClCl H H H CH═CHCH₂NEt₂ 130-131 110 NMe Me Me H H H Me 200 111 NMe Cl Cl HH Me CH═CHCH₂(4-Me-piperazin-4-yl) 251-253 112 NMe Cl Cl H H MeCH═CHCH₂(piperidin-1-yl) 159-161 113 NMe Cl Cl H H MeCH═CHCH₂N(Et)(CH₂CH₂OH) 220-222 114 NMe Cl Cl H H Me CH═CHCH₂N(Me)(OH)185-186 115 NMe Cl Cl H H Me CH═CHCH₂(3-OH-pyrrolidin-1-yl) 160-163 116NMe Cl Cl H H Me CH═CHCH₂N(n-Bu)₂ 122-125 117 NMe Cl Cl H H MeCH═CHCH₂N(Me)(MeOCH₂—CH₂) 125-127 118 NMe Me Me H H Me CH═CHCH₂NEt₂185-191 119 NMe Cl Cl H H Me CH═CHCH₂N(Me)(Et₂NCH₂—CH₂) 119-121 120 NMeCl Me H H Me CH═CHCH₂NEt₂ 130-132 121 NMe Cl Cl H H MeCH═CHCH₂N(Me)((CH₂)₃NMe₂) 116-119 122 NMe Cl Cl H H MeCH═CHCH₂SCH₂CH₂NEt₂ 141-146 123 NMe Cl Cl H H Me CH═CHCH₂NMe₂ 245-247124 NMe Cl Cl H H Me CH═CHCH₂N(Me)(cyclohexyl) 148-151 125 NMe Cl Cl H HMe CH═CHCH₂N(Me)(i-Pr) 155-157 126 NMe H H H H Me Me 280 dec 127 NMe HCl H H Me Me 240 dec 128 NMe H H Cl H Me Me >300 129 NMe Cl Cl Cl H MeMe >300 130 NMe Cl H H H Me CH═CHCH₂NEt₂ 144-146 131 NMe Cl Cl Cl H MeCH═CHCH₂NEt₂ 197-199 132 NMe H H H H Me CH═CHCH₂NEt₂ 172-175 133 NH ClCl H H Me 5-oxazolyl >300 134 NMe Cl Cl H H Me CN >300 135 NMe Cl Cl H HMe

135-137 136 NMe Cl Cl H H Me

186-188 137 NMe Cl Cl H H Me

289-290 138 NMe Cl Cl H H Me CH═CHCH₂-(3-NH2CO-piperidin-1-yl) 182-184139 NMe Cl Cl H H Me CH═NNMe₂ >300 140 NMe Cl Cl H H Me CH═NNHMe 295-299141 NMe Cl Cl H H Me CH₂OC(O)Me >285 142 NMe Cl Cl H H MeCH═CHCH₂-(3-NH2-pyrrolidin-1-yl) 200-202 143 NMe Cl Cl H H MeCH═CHCH₂-(3-MeC(O)NH-pyrrohdin-1-yl) 237-239 144 NMe Cl Cl H H MeCH═CHCH₂-(3-NMe₂-pyrrolidin-1-yl) 189-191 145 NMe Cl Cl H H MeCH═CHCH₂-(2-NH₂CO-piperidin-1-yl) 202-204 146 NMe Cl Cl H H MeCH═N(pyrrolidin-1-yl) 285-295 dec 147 NMe Cl Cl H H Me CH═NNHC(O)NH₂267-270 dec 148 NMe Cl Cl H H Me C(O)NH₂ dec >228 149 NMe Cl Cl H H Me2,3-dihydrobenzimidazol-2-yl dec. >240 150 NMe Cl Cl H H MeBenzimidazol-2-yl 248-252 151 NMe Cl Cl H H Me CH═NMHPh >300 152 NMe ClCl H H Me

264-265 153 NMe Cl Cl H H Me CH═CHCH₂(3-NH₂CH₂-piperidin-1-yl) 163-165154 NMe Cl Cl H H Me CH═CHCH₂(3-NEt₂C(O)-piperidin-1-yl) 169-171 155 NMeCl Cl H H Me 5-NH₂-benzimidazol-2-yl dec. 290 156 NMe Cl Cl H H Me2,3-dihydro-1H-imidazo[4,5-c]pyridin-2-yl >300 157 NMe Cl Cl H H Meimidazo[4,5-c]pyridin-2-yl >300 158 NMe Cl Cl H H Me4-NH₂-benzimidazol-2-yl dec >290 159 NMe Cl Me NH₂— H Me Me >300 C(O)160 NMe Cl Cl H H Me C≡CH dec. >290 161 NMe Cl Cl H H MeCH═CHCH₂NHC(O)NHMe >290 162 NMe Cl Cl CF₃ H Me Me >300 163 NMe Cl Cl H HMe CH(OH) cyclopentyl 285 (dec.) 164 NMe Cl Cl H H MeCH═CHCH₂NHC(O)cyclohexyl >290 165 NMe Cl Cl H H MeCH═CHCH₂NHC(O)NH[2-MeOC(O)]Ph >290 166 NMe Cl Cl H H Me CH═CHCH₂NHC(O)NH[3-CN]Ph >300 167 NMe Cl Cl H H H Ph >250(dec) 168 NMe Cl Cl H HMe CH═CHCH₂NHC(O)Ph >290 169 NMe Cl Cl H H MeCH═CHCH₂NHC(O)NH[3-EtOC(O)]Ph >290 170 NMe Cl Cl H H Me Ph >300 171 NMeCl Cl H H EtOC(O) Ph 283-284 172 NMe Cl Cl H H MeCH═CHCH₂NHC(O)NH[3-NO₂]Ph >290 173 NMe Cl Cl H H MeCH═CHCH₂NHC(O)NH[2-NO₂]Ph >290 174 NMe Cl Cl H H MeCH═CHCH₂NHS(O)₂Me >290 175 NMe Cl Cl H H Me CH═CHCH₂NHC(O)NH₂ >290 176NMe Cl Cl H H Me (cyclopenten-1-yl)CH₂ — 177 NMe Cl Cl H H Me(cyclopentylidene-1-yl)CH — 178 NMe Cl Cl H H MeCH═CHCH₂NHC(O)NH(cyclohexyl) >290 179 NMe Cl Cl H H MeCH═CHCH₂NHSO₂Ph >290 180 NMe Me Me OMe H Me Me 181 NMe Cl Cl H H MeCH═CHCH₂NHEt 218-221 182 NMe Cl Cl H H Me CH═CHCH₂NHC(═NH)NH₂ >290 183NMe Cl Cl H H Me CH═CHCH₂(2,4-dioxo-quinazolin-3-yl) >290 184 NMe Cl ClH H Me (3-CO₂H)Ph >300 185 NMe Cl Cl H H Me (3-Br)Ph >300 186 NMe Cl ClH H Me CH═CHCH₂NHC(O)(piperidin-3-yl) >290 187 NMe Cl Cl H H Me

279-282 188 NMe Cl Cl H H Me

189 NMe Cl Cl H H Me [3-NH₂C(O)]Ph >300 190 NMe Cl Cl H H Me

>290 191 NMe Cl Cl H H Me CH═CHCH₂NH C(O)(piperidin-2-yl) 269-273 192NMe Cl Cl H H Me (3-CN)Ph >300 193 NMe Cl Cl H H Me (3-NH₂CH₂)Ph 241-246194 NH Me Me OMe H Me Me foam 195 NMe Cl Cl H H Me (3-NH₂C(═NH)NHCH₂)Ph245-253 196 NPr Cl Cl H H Me Me 280-281 197 NEt Cl Cl H H Me Me >300

[0606] TABLE 4 Compounds of Formula I with R₄, R₅ = B

Ex. X Ar₁ R_(a) R₈ R₉ m.p. ° C. 198 NH

H Me Me >300 199 NH

H Me Me >300 200 NMe

H Me Me 335(dec) 201 NMe

H Me Me 295(dec) 202 NMe

H Me Me 268-269 203 NMe

H Me Me >300 204 NMe

H Me CH═CHCH₂NEt₂ 250(dec) 205 NMe

H Me Me >300

[0607] TABLE 5 Compounds of Formula I wherein R₄, R₅ = B and R₈ and R₉together form a ring

Ex X R₁ R₂ R₃ R_(a) R₈ and R₉ m.p. ° C. 206 NMe Cl Cl H H

>300 207 NMe Cl Cl H H

>300 208 NMe Cl Cl H H

>300 209 NMe Cl Cl H H

>300 210 NMe Cl Cl H H

foam 211 NMe Cl Cl H H

>300 212 NMe Cl Cl H H

>300

[0608] Assessment of Biological Properties

[0609] Tyrosine Kinase Inhibition Assay

[0610] The inhibition of tyrosine kinases by the compounds of theinvention was measured with the following assay.

[0611] Kinase Reaction Buffer 50 mM Hepes, pH 7.5, 50 mM KCl, 25 mMMgCl₂, 5 mM MnCl₂, 100 pM, Na₃VO₄, 0.01% CHAPS, 1 mM DTT, and 50 mg/mLBSA, Adenosine 5′-Triphosphate (ATP) solution at 100 mM, pH 7.5-,γ33P-ATP, 2000 Ci/mmol at 10 μCi/μl,-Poly(L-glutamic acid-L-tyrosine,4:1) or (E4Y)_(n) at 10 mg/mL in water.

[0612] Assay: Test compounds, obtained routinely at 5mg/mL in 100% DMSOwere diluted appropriately into complete Kinase assay buffer with 10%DMSO, 10 μl of the 6Xcompound solution was distributed into each assaywell, the final compound concentration for IC₅₀ determinations rangedfrom 200 to 1 μg/mL. [γ33P]-ATP label was prepared as a 10 Ci/mmolworking solution in complete Kinase assay buffer. Protein kinase wasinitiated by adding 10 to 50ηg of diluted enzyme stock.

[0613] Plates were incubated at 30 ° C. for 30 min. During theincubation period, the MultiScreen harvest plates were pre-wetted with10% TCA/5% Ppi. 150 μl of TCA/PPi was added to all MultiScreen platewells after pre-wetting. The kinase reaction was stopped via replicatransfer of the polypropylene reaction wells into the MultiScreenplates. The plates were incubated at room temperature for 5 min thenvacuum harvested and washed with 200 μl TCA/PPi 3-4 times per well, then100 μl of cocktail per well was added.

[0614] Experimental data consisted of eight (8) compound doses induplicate with ten (10) enzyme control reaction wells (so-called totals)and six (6) background wells. The results were obtained as percentinhibition (mean with S.D.) over the full compound dose range. IC₅₀potency estimates are determined using a floating inhibition maximum(Imax).

[0615] All compounds in the synthetic examples and Tables above wereevaluated in the tyrosine kinase assay above using a kinase such as p56lck and were found to have IC₅₀'s less than 10 μM.

[0616] Representative compounds from the examples above were evaluatedin the tyrosine kinase assay above using p60 src and were found to haveIC₅₀'s less than 10 μM.

[0617] Representative compounds from the examples above were evaluatedin the tyrosine kinase assay above using PDGFR kinase and were found tohave IC₅₀'s less than 10 μM.

[0618] Inhibition of IL-2 Production

[0619] Inactivation of T cells resulting from inhibition of the tyrosinekinase p56 lck can be measured by inhibition of IL-2 production inJurkat cells. 96-well flat bottom plates were coated with anti-CD3,clone UCHT1, (Immunotech cat. # 1304) at 4 μg/ml in Phosphate BufferedSaline (PBS), 100 μl/well. The solution was prepared by taking 200 μl of200 μg/ml anti-CD3 stock/10 ml PBS. The plate was then incubated at 37°C. for 2 h. Jurkat cells were pelleted and counted. The cells wereresuspended at 2.5×10⁶ cells/ml in RPMI, 10% FBS (complete media). Testcompounds were diluted from a 5 mg/ml DMSO stock directly into completemedia.

[0620] 10 μl of 20 X compound/ well was added to a separate plate,followed by 100μl of cell suspension in triplicate and this plate waspreincubated at 37° C. for 30min. The 96-well plate containing anti-CD3was aspirated, and the cells and compound transferred to this plate. 100μl of PMA (Phorbol 12-Myristate 13-Acetate, Sigma cat.# P-8139) at 20ng/ml was added, and the plate was incubated overnight at 37° C. (PMAstock at 1 mg/ml in ethanol, dilute 10 μl/ml in complete media, then 20μl/10 mls. in complete media. 100 μl/well=10 ng/ml. finalconcentration). The next day, the plate was centrifuged at 1500 rpm for5 min. at room temperature and the supernatants were removed. Thesupernatants were tested using R&D Systems Quantikine Human IL-2 Kit(cat.#2050). Samples were diluted 1:5 in RPMI1640, and 100 μl/well usedin the ELISA. The optical density of each well was determined using amicroplate reader set to 450 nm. EC₅₀ values were determined usingOrigin (non-linear regression) or SAS by plotting absorbance vs.concentration of compound.

[0621] Representatives from the synthetic examples and the Tables abovewere screened in this assay and had IC_(50')s below 10 μM.

We claim:
 1. A Compound of the formula(I):

wherein: Ar₁ is an aromatic or nonaromatic carbocycle, heteroaryl orheterocycle; wherein said carbocycle, heteroaryl or heterocycle isoptionally substituted by one or more R₁, R₂ and R₃; X is NH,N—C₁₋₃alkyl, N-cyclopropyl, S or O; Y is NR₁₅, S or O; R_(a) is H,C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₁₀alkynyl, each of which may be branchedor cyclic; or R_(a) is aryl or heteroaryl; wherein each R_(a) isindependently optionally substituted with one or more C₁₋₆alkyl, C₁₋₆alkoxy, halogen, OH, oxo, NR₁₀R₁₁, aryl or heteroaryl each aryl orheteroaryl being optionally substituted with one or more groups selectedfrom halogen, OH, C₁₋₃alkyl, C₁₋₃alkoxy, hydroxyC₁₋₃alkyl and(CH₂)_(m)NR₁₀R₁₁; and wherein R_(a) is attached at the 4- or 5-position; R₁ and R₂ are the same or different and selected from H,halogen, CN, NO₂, C₁₋₁₀ branched or unbranched saturated or unsaturatedalkyl, C₁₋₁₀ branched or unbranched alkoxy, C₁₋₁₀ branched or unbranehedacyl, C₁₋₁₀ branched or unbranched acyloxy, C₁₋₁₀ branched or unbranchedalkylthio, aminosulfonyl, di-(C₁₋₃)alkylaminosulfonyl, NR₁₀R₁₁, aryl,aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy; wherein theabovementioned R₁ and R₂ are optionally partially or fully halogenatedor optionally substituted with one to three groups independentlyselected from oxo, OH, NR₁₀R₁₁, C₁₋₆ branched or unbranched alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- ordi(C₁₋₃)alkylaminocarbonyl; R₃ is H, halogen, OH, (CH₂)_(n)NR₁₀R₁₁,CONR₁₀R₁₁, (CH₂)_(n)CO₂R₁₂; C₁₋₃alkyl optionally substituted with OH,C₁₋₃ alkoxy optionally halogenated or C₁₋₃ alkylthio; R₄ and R₅ togetherwith the atoms to which they are attached complete a fused ring systemof the formulas A or B:

R₆ IS C₁₋₃alkyl or H; R₇ is C₁₋₆alkyl branched or unbranched or H; R₈ isH, C₁₋₆alkyl branched or unbranched, saturated or unsaturated,optionally substituted with phenyl, OH or C₁₋₃alkoxy; or R₈ is(CH₂)_(m)NR₁₀R₁₁, (CH₂)_(m)NR₁₀COR₁₂, (CH₂)_(n)CO₂R₁₂,(CH₂)_(n)CONR₁₀R₁₁; or R₈ is phenyl or heteroaryl, each being optionallysubstituted with C₁₋₃alkyl, C₁₋₃alkoxy, OH, —SO₃H or halogen; R₉ is H,CN or CONR₁₀R₁₁; or R₉ is C₁₋₁₀alkyl branched or unbranched,C₃₋₁₀cycloalkyl, C₅₋₇cycloalkenyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl each beingoptionally substituted with one or more C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkylidene, C₅₋₇cycloalkenyl, halogen, OH, oxo, CN,C₁₋₃alkoxy, C₁₋₃acyloxy, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀C(═NR₁₀)NR₁₀R₁₁,NR₁₀COR₁₂, NR₁₀S(O)_(p)R₁₂, SR₁₂, CONR₁₀R₁₁, CO₂R₁₂, C(R₁₀)═NNR₁₀R₁₁,C(R₁₀)═NNR₁₀CONR₁₀R₁₁, aryloxy, arylthio, aryl or heteroaryl; whereineach aryloxy, arylthio, aryl or heteroaryl is optionally substitutedwith C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(n)NR₁₀R₁₁ or O(CH₂)₂₄NR₁₀R₁₁; or R₉ is aryl, heteroaryl, or heterocycle, wherein each aryl,heteroaryl or heterocycle is optionally substituted with one to threegroups selected from C₁₋₃alkyl optionally substituted with phenyl orNR₁₀C(═NR₁₀)NR₁₀R₁₁, C₁₋₃alkoxy, halogen, CN, oxo, (CH₂)_(n)NR₁₀R₁₁,(CH₂)_(n)CO₂R₁₂; (CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁; or R₈ and R₉together form a saturated or unsaturated 5 or 6 membered aromatic ornonaromatic carbocyclic ring optionally substituted by one or twoC₁₋₃alkyl, OH, oxo or (CH₂)_(n)NR₁₀R₁₁, or optionally spiro-fused to a1,3 dioxolane group or 1,3 dithiolane group, each 1,3 dioxolane group or1,3 dithiolane group optionally substituted by C₁₋₆alkyl, C₁₋₆alkoxy, OHor (CH₂)_(n)NR₁₀R₁₁; R₁₀ and R₁₁ may be the same or different and areeach independently selected from H, OH, C₁₋₃alkoxy, C₁₋₆alkyl branchedor unbranched, C₃₋₈cycloalkyl, aryl, arylC₁₋₃alkyl and heteroaryl;wherein said alkyl, cycloalkyl, aryl, arylC₁₋₃alkyl or heteroaryl areoptionally substituted with OH, C₁₋₃alkoxy, CN, NO₂, C₁₋₃acyloxy,CO₂R₁₂, NR₁₃R₁₄, O(CH₂)₂₋₄NR₁₃R₁₄, aryl or heteroaryl; or R₁₀ and R₁₁together form a 3-7 member alkylene chain completing a ring about the Natom to which they are attached; wherein said alkylene chain isoptionally interrupted by O, S(O)_(p), and NR₁₃; and wherein said ringis optionally substituted by C₁₋₃ alkyl, C₁₋₃alkoxy, OH,—(CH₂)_(n)NR₁₃R₁₄, CONR₁₃R₁₄ or NR₁₃COR₁₄; R₁₂ is H, C₁₋₆alkyl orC₃₋₈cycloalkyl wherein each alkyl or cycloalkyl is optionallysubstituted with phenyl, OH, C₁₋₃alkoxy or NR₁₃R₁₄; or R₁₂ is phenyl orheterocycle, optionally substituted with one to three groups selectedfrom C₁₋₃alkyl, C₁₋₃alkoxy, halogen, (CH₂)_(m)NR₁₀R₁₁,(CH₂)_(n)CONR₁₀R₁₁ and O(CH₂)₂₋₄NR₁₀R₁₁; R₁₃ and R₁₄ are eachindependently selected from H and C₁₋₆ alkyl optionally substituted withC₁₋₃alkoxy, OH or phenyl; or R₁₃ and R₁₄ together form a chaincompleting a ring, said chain is (CH₂)₄₋₅ or (CH₂)₂O(CH₂)₂; R₁₅ is H orC₁₋₃ alkyl; m is 1-4; n is 0-3 and p is 0-2; and the pharmaceuticallyacceptable acid or salt derivatives thereof.